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 3β, 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.
Highlights
Aging is a fundamental and complex physiological process that compromises health, causing multiple chronic diseases
We focus on recent progress in research on the Kelch-like ECH-associated protein 1- (Keap1-)nuclear factor-erythroid 2-related factor 2 (Nrf2) system involving oxidative stress and aging, providing an empirical basis for the development of antiaging drugs
The mice exhibited attenuated NAD(P)H:quinone oxidoreductase 1 (NQO1) expression and higher intracellular oxidant levels [74]. These results suggest that p62 may exert its antiaging effects through Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 signaling
Summary
Aging is a fundamental and complex physiological process that compromises health, causing multiple chronic diseases. Nuclear factorerythroid 2-related factor 2 (Nrf2) is a master regulator of multiple antioxidant enzymes; it modulates cell redox balance and senses the status of cellular oxidative stress. This is done by stimulating the activity of components of antioxidant defense, such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), heme oxygenase-1 (HO-1), glutathione reductase, thioredoxin reductase, ferritin, and NAD(P)H:quinone oxidoreductase 1 (NQO1) [18, 19]. Researchers are currently working to identify candidate antioxidant-related agents that activate Nrf for development into antiaging drugs and for treating aging-related diseases These efforts are largely dependent on elucidating the correlation between Keap1-Nrf signaling and oxidative stress. In this review, we present a compilation of the regulation of Keap1-Nrf signaling to provide new ideas for the identification and development of antiaging agents
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