The KEAP1-NRF2 System in Healthy Aging and Longevity

Matsumaru, Daisuke; Motohashi, Hozumi

doi:10.3390/antiox10121929

Cited by 53 publications

(39 citation statements)

References 190 publications

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“…Activation of the p62/Nrf2/Keap1 pathway increases the antioxidant capacity of cells and inhibits the occurrence of ferroptosis ( Sun et al, 2016 ). When stimulated by oxidative distress, Nrf2 undergoes nuclear translocation and binds to antioxidant response element (ARE) to initiate transcription of a variety of cytoprotective genes ( Matsumaru and Motohashi, 2021 ). For example, Nrf2 regulates the expression of FTH and FTL for iron storage, FPN and TFRC for iron transport, and HO-1 for intracellular iron production, therefore controlling cellular iron metabolism ( Zhao et al, 2021 ).…”

Section: The Process and Regulation Of Ferroptosismentioning

confidence: 99%

Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases

Sun

Xia

Basnet

et al. 2022

Front. Aging Neurosci.

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Neurodegenerative diseases are a diverse class of diseases attributed to chronic progressive neuronal degeneration and synaptic loss in the brain and/or spinal cord, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis. The pathogenesis of neurodegenerative diseases is complex and diverse, often involving mitochondrial dysfunction, neuroinflammation, and epigenetic changes. However, the pathogenesis of neurodegenerative diseases has not been fully elucidated. Recently, accumulating evidence revealed that ferroptosis, a newly discovered iron-dependent and lipid peroxidation-driven type of programmed cell death, provides another explanation for the occurrence and progression of neurodegenerative diseases. Here, we provide an overview of the process and regulation mechanisms of ferroptosis, and summarize current research progresses that support the contribution of ferroptosis to the pathogenesis of neurodegenerative diseases. A comprehensive understanding of the emerging roles of ferroptosis in neurodegenerative diseases will shed light on the development of novel therapeutic technologies and strategies for slowing down the progression of these diseases.

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Section: The Process and Regulation Of Ferroptosismentioning

confidence: 99%

Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases

Sun

Xia

Basnet

et al. 2022

Front. Aging Neurosci.

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“…A large number of studies have described the involvement of the Nrf2 antioxidant system in the prevention or attenuation of age-related diseases including atherosclerosis, vascular calcification, cataract formation, and macular degeneration [ 21 , 25 , 33 , 46 , 47 , 48 ]. There are numerous clinical trials targeting the Nrf2 system in diverse clinical conditions including cancer, chronic kidney disease, diabetes, aging problems, etc.…”

Section: Discussionmentioning

confidence: 99%

Activation of Nrf2/HO-1 Antioxidant Pathway by Heme Attenuates Calcification of Human Lens Epithelial Cells

et al. 2022

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Cataract, an opacification in the crystalline lens, is a leading cause of blindness. Deposition of hydroxyapatite occurs in a cataractous lens that could be the consequence of osteogenic differentiation of lens epithelial cells (LECs). Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the transcription of a wide range of cytoprotective genes. Nrf2 upregulation attenuates cataract formation. Here we aimed to investigate the effect of Nrf2 system upregulation in LECs calcification. We induced osteogenic differentiation of human LECs (HuLECs) with increased phosphate and calcium-containing osteogenic medium (OM). OM-induced calcium and osteocalcin deposition in HuLECs. We used heme to activate Nrf2, which strongly upregulated the expression of Nrf2 and heme oxygenase-1 (HO-1). Heme-mediated Nrf2 activation was dependent on the production of reactive oxygens species. Heme inhibited Ca deposition, and the OM-induced increase of osteogenic markers, RUNX2, alkaline phosphatase, and OCN. Anti-calcification effect of heme was lost when the transcriptional activity of Nrf2 or the enzyme activity of HO-1 was blocked with pharmacological inhibitors. Among products of HO-1 catalyzed heme degradation iron mimicked the anti-calcification effect of heme. We concluded that heme-induced upregulation of the Nrf2/HO-1 system inhibits HuLECs calcification through the liberation of heme iron.

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“…Under normal physiological conditions, Nrf2 binds to the cytoplasmic inhibitor, Keap1, and exists in the cytoplasm, maintaining low transcriptional activity ( Luo et al, 2021 ). However, under oxidative stress, Nrf2 translocates to the nucleus, binds to Marf proteins to form a heterodimer, and then binds to anti-oxidant response elements (AREs) to activate the expression of anti-oxidation genes ( Matsumaru and Motohashi, 2021 ). Oxidative stress increased the mRNA level of the oxidation-promoting factor, keap1 , which was inhibited by TGGR intervention.…”

Section: Discussionmentioning

confidence: 99%

Studies on the Regulation and Molecular Mechanism of Panax Ginseng Saponins on Senescence and Related Behaviors of Drosophila melanogaster

Zhao

Liu

Zhang

et al. 2022

Front. Aging Neurosci.

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In an increasingly aged global population, achieving healthy life expectancy through natural and safe drug interventions is highly desirable. Here we show that total ginsenosides (TGGR), the main active components in the traditional Chinese medicine, ginseng, promote longevity across species. In Drosophila, an intriguing effect of TGGR on lifespan was the relatively narrow treatment window to elicit long-term benefits. TGGR administration during early adulthood, and especially during midlife, was sufficient to extend lifespan in both sexes. TGGR did not increase lifespan by reducing food intake or reproductive capacity; rather, TGGR increased the fertility of male Drosophila. TGGR augmented healthspan readouts associated with youth and with healthy aging, such as motility, intestinal barrier integrity, and biorhythm homeostasis. TGGR treatment also improved some types of stress resistance in both sexes, including increased tolerance to starvation and oxidation, and shifting “aged” gene expression patterns toward “healthy” patterns seen in the young. Gene expression, pharmacological and genetic epistatic analyses demonstrated that TGGR effects require normal expression of genes involved in insulin, TOR and MAPK signaling. The positive effects of TGGR on both healthspan and lifespan, coupled with its mechanism of action via evolutionarily conserved signaling pathways, demonstrate it to be a promising anti-aging drug.

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The KEAP1-NRF2 System in Healthy Aging and Longevity

Cited by 53 publications

References 190 publications

Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases

Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases

Activation of Nrf2/HO-1 Antioxidant Pathway by Heme Attenuates Calcification of Human Lens Epithelial Cells

Studies on the Regulation and Molecular Mechanism of Panax Ginseng Saponins on Senescence and Related Behaviors of Drosophila melanogaster

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