The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging

Yu, Chao; Xiao, Jian-Hui

doi:10.1155/2021/6635460

Cited by 537Genomics, phytochemicals, and oxidative stressGenetics, Aging, and Longevity in Model OrganismsRedox biology and oxidative stress

The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging

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Yu, Chao, Xiao, Jian-Hui·2021·Oxidative Medicine and Cellular Longevity

DOI 10.1155/2021/6635460PMC PMC8106771

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Abstract

Oxidative stress, a term that describes the imbalance between oxidants and antioxidants, leads to the disruption of redox signals and causes molecular damage. Increased oxidative stress from diverse sources has been implicated in most senescence‐related diseases and in aging itself. The Kelch‐like ECH‐associated protein 1‐ (Keap1‐) nuclear factor‐erythroid 2‐related factor 2 (Nrf2) system can be used to monitor oxidative stress; Keap1‐Nrf2 is closely associated with aging and controls the transcription of multiple antioxidant enzymes. Simultaneously, Keap1‐Nrf2 signaling is also modulated by a more complex regulatory network, including phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt), protein kinase C, and mitogen‐activated protein kinase. This review presents more information on aging‐related molecular mechanisms involving Keap1‐Nrf2. Furthermore, we highlight several major signals involved in Nrf2 unbinding from Keap1, including cysteine modification of Keap1 and phosphorylation of Nrf2, PI3K/Akt/glycogen synthase kinase 3 β , sequestosome 1, Bach1 , and c ‐ Myc . Additionally, we discuss the direct interaction between Keap1‐Nrf2 and the mammalian target of rapamycin pathway. In summary, we focus on recent progress in research on the Keap1‐Nrf2 system involving oxidative stress and aging, providing an empirical basis for the development of antiaging drugs.

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A SASP profile can be determined by activation of molecular cascades linked to p53/p21 due to persistent double strand breaks or telomere shortening.
“A SASP profile can be further determined by the activation of molecular cascades linked to p53/p21 (due to persistent double strands breaks/telomere shortening)”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [22]
A SASP profile can be promoted by failure of the antioxidant cascade due to defects in Nrf2.
“a SASP profile can be promoted both by the failure of the antioxidant cascade due to defects in the well-known transcriptional factor Nrf2 (nuclear factor erythroid 2–related factor 2) [22]”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [22]
A SASP profile can be determined by activation of p16/Rb due to epigenetic modifications.
“but also to p16/Rb (due to epigenetic modifications) [3,22,24,25,26]”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [22]

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Regulation of Nrf2/ARE Pathway by Dietary Flavonoids: A Friend or Foe for Cancer Management?
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Hyperoxia Stimulates an Nrf2-ARE Transcriptional Response via ROS-EGFR-PI3K-Akt/ERK MAP Kinase Signaling in Pulmonary Epithelial Cells
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Novel target for treating Alzheimer’s Diseases: Crosstalk between the Nrf2 pathway and autophagy
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Flavonoids and platelet aggregation: A brief review
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iASPP Is an Antioxidative Factor and Drives Cancer Growth and Drug Resistance by Competing with Nrf2 for Keap1 Binding
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SQSTM1/p62 and PPARGC1A/PGC-1alpha at the interface of autophagy and vascular senescence
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Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1
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Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 via stimulating the Akt/GSK-3ß/Fyn pathway
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GSK-3α is a central regulator of age-related pathologies in mice
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Are Astrocytes the Predominant Cell Type for Activation of Nrf2 in Aging and Neurodegeneration?
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Curcumin exerts a protective effect against premature ovarian failure in mice
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Epigallocatechin gallate upregulates NRF2 to prevent diabetic nephropathy via disabling KEAP1
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Resveratrol attenuates testicular apoptosis in type 1 diabetic mice: Role of Akt-mediated Nrf2 activation and p62-dependent Keap1 degradation
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Aging-related decline in the induction of Nrf2-regulated antioxidant genes in human bronchial epithelial cells
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Neuroprotective Effect of Caffeic Acid Phenethyl Ester in A Mouse Model of Alzheimer’s Disease Involves Nrf2/HO-1 Pathway
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C‐Myc is a Nrf2‐interacting protein that negatively regulates phase II genes through their electrophile responsive elements
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Sustained Activation of Nuclear Erythroid 2-Related Factor 2/Antioxidant Response Element Signaling Promotes Reductive Stress in the Human Mutant Protein Aggregation Cardiomyopathy in Mice
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KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients
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Assurance of mitochondrial integrity and mammalian longevity by the p62–Keap1–Nrf2–Nqo1 cascade
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ER Stress Inhibits mTORC2 and Akt Signaling Through GSK-3β–Mediated Phosphorylation of Rictor
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Baicalein and baicalin alleviate acetaminophen-induced liver injury by activating Nrf2 antioxidative pathway: The involvement of ERK1/2 and PKC
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Protection of Kaempferol on Oxidative Stress‐Induced Retinal Pigment Epithelial Cell Damage
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The autophagy receptor p62/SQST-1 promotes proteostasis and longevity in C. elegans by inducing autophagy
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Neuroprotective effect of phosphocreatine on oxidative stress and mitochondrial dysfunction induced apoptosis in vitro and in vivo: Involvement of dual PI3K/Akt and Nrf2/HO-1 pathways
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Multiple myeloma cell survival relies on high activity of protein kinase CK2
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Antisense oligonucleotide against GSK-3β in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: Involvement of transcription factor Nrf2 and implications for Alzheimer disease
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Regulation of Angiogenesis by Glycogen Synthase Kinase-3β
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Hydrogen Sulfide Alleviates Liver Injury Through the S‐Sulfhydrated‐Kelch‐Like ECH‐Associated Protein 1/Nuclear Erythroid 2–Related Factor 2/Low‐Density Lipoprotein Receptor–Related Protein 1 Pathway
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Nrf2 Signaling and the Slowed Aging Phenotype: Evidence from Long-Lived Models
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A literature review of flavonoids and lifespan in model organisms
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Fibroblast growth factor (FGF21) protects mouse liver against d-galactose-induced oxidative stress and apoptosis via activating Nrf2 and PI3K/Akt pathways
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Dietary Polyphenols in Age-Related Macular Degeneration: Protection against Oxidative Stress and Beyond
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GSK3β-mediated Keap1-independent regulation of Nrf2 antioxidant response: A molecular rheostat of acute kidney injury to chronic kidney disease transition
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Exercise-induced Nrf2-signaling is impaired in aging
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C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape
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Four-octyl itaconate activates Keap1-Nrf2 signaling to protect neuronal cells from hydrogen peroxide
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Resveratrol mitigates the oxidative stress mediated by hypoxic-ischemic brain injury in neonatal rats via Nrf2/HO-1 pathway
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Bergenin impedes the generation of extracellular matrix in glomerular mesangial cells and ameliorates diabetic nephropathy in mice by inhibiting oxidative stress via the mTOR/β-TrcP/Nrf2 pathway
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Nrf2 Transcription Factor Can Directly Regulate mTOR
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A Muscle-Specific p38 MAPK/Mef2/MnSOD Pathway Regulates Stress, Motor Function, and Life Span in Drosophila
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Inhibiting microRNA-144 potentiates Nrf2-dependent antioxidant signaling in RPE and protects against oxidative stress-induced outer retinal degeneration
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AMPK/p38/Nrf2 activation as a protective feedback to restrain oxidative stress and inflammation in microglia stimulated with sodium fluoride
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Modulation of telomere protection by the PI3K/AKT pathway
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Dihydroquercetin Activates AMPK/Nrf2/HO-1 Signaling in Macrophages and Attenuates Inflammation in LPS-Induced Endotoxemic Mice
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Modulation of Keap1/Nrf2/ARE Signaling Pathway by Curcuma- and Garlic-Derived Hybrids
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Aging related changes in circulating reactive oxygen species (ROS) and protein carbonyls are indicative of liver oxidative injury
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p62/SQSTM1 protects against cisplatin-induced oxidative stress in kidneys by mediating the cross talk between autophagy and the Keap1-Nrf2 signalling pathway
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Protein Kinase CK2 Regulates Cytoskeletal Reorganization during Ionizing Radiation–Induced Senescence of Human Mesenchymal Stem Cells
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Astaxanthin Protects Retinal Photoreceptor Cells against High Glucose-Induced Oxidative Stress by Induction of Antioxidant Enzymes via the PI3K/Akt/Nrf2 Pathway
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A Solid Dispersion of Quercetin Shows Enhanced Nrf2 Activation and Protective Effects against Oxidative Injury in a Mouse Model of Dry Age-Related Macular Degeneration
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Flavonoids as Putative Inducers of the Transcription Factors Nrf2, FoxO, and PPARγ
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Baicalin Ameliorates Liver Injury Induced by Chronic plus Binge Ethanol Feeding by Modulating Oxidative Stress and Inflammation via CYP2E1 and NRF2 in Mice
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Activation of a Novel c-Myc-miR27-Prohibitin 1 Circuitry in Cholestatic Liver Injury Inhibits Glutathione Synthesis in Mice
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6-bromo-indirubin-3′-oxime (6BIO), a Glycogen synthase kinase-3β inhibitor, activates cytoprotective cellular modules and suppresses cellular senescence-mediated biomolecular damage in human fibroblasts
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The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence
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Authors: Yu, C., & Xiao, J.-H.
Affiliations: Zunyi Medical University (CN)
Corresponding author: Xiao, Jian-Hui
ORCID: Yu, Chao
Xiao, Jian-Hui
Venue: Oxidative Medicine and Cellular Longevity
Publisher: Wiley
Published: 2021-01
Volume: 2021
Issue: 1
Pages: 6635460-6635460
ISSN: 1942-0994 (ISSN-L)
1942-0900
DOI: 10.1155/2021/6635460
PMC: PMC8106771
OpenAlex: W3155261830
Cited by: 537
References: 211
Citations by year: 2026: 120 · 2025: 129 · 2024: 121 · 2023: 90 · 2022: 66 · 2021: 11
FWCI: 7.74
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor, 109 d)
Locations: Oxidative Medicine and Cellular Longevity (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders: National Natural Science Foundation of China (31960191)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords: oxidative stress, aging, senescence, antioxidant enzymes, PI3K/Akt signaling, glycogen synthase kinase-3β, p62, BACH1, c-Myc, mTOR signaling, Nrf2 phosphorylation, cysteine modification, anti-aging drugs
MeSH terms: Kelch-Like ECH-Associated Protein 1, Aging, Animals, Humans, Oxidative Stress, NF-E2-Related Factor 2, Rats

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The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging

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