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Role of Nrf2 in aging:
[edit]Nrf2 signaling and its function is altered with age which is believed to be responsible for aging phenotype[1]. With the alteration of Nrf2 activity, and knowing that aging also associated with accumulation of oxidants and free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), the risk of oxidative damage increases and leads to the development of chronic diseases such as cardiovascular diseases, neurodegenerative diseases, and cancer[2][1]. The data on this matter various depending on in which cells and tissues the nrf2 activity has been studied[2].
In a study that looked at the differences in cardiac Nrf2-ARE binding activity between young mice (8-10 weeks old) and old mice (⪰23 months); both groups had wild-type mice and Nrf2 knockout mice[3]. The results show a significant decrease of Nrf2-ARE signaling in the aging heart [3][2]. Moreover, when exposing old mice to acute exercise or endurance exercise stress, their heart developed oxidative stress due to the diminished function of Nrf2. on the other hand, exposing the old mice to prolonged and moderate exercise helped to stabilize the Nrf2 function level which points out the potential benefit of non-pharmacological approaches to optimize the Nrf2-signaling pathway to minimize aging oxidative stress[3]. Another study looked at the Nrf2 activity in aging liver of rats and examined the Nrf2 activity at cellular and nuclear levels[4]. The analysis demonstrated a decline in hepatic Nrf2 levels in old rats at both cellular and nuclear levels when compared to young rats[4]. This indicates that aging has an adverse effect on basal Nrf2-mediated gene transcription[4]. In a study that was the first to look at the role of Nrf2/Keap1 signaling in human skeletal muscle and investigate the relationship between Nrf2 activity and the impaired oxidative stress response in skeletal muscle with aging, active young university students, active old adults and sedentary old adults were recruited[5]. Altered regulation of Nrf2/Keap1 redox signaling was noted in the skeletal muscle tissue of the sedentary old group[5]. Moreover, when comparing the Nrf2 protein contents among the three groups, the active old group showed a significant higher contents than the other groups[5].
These studies along with others that investigate the effect of nrf2 activation on aging and age-associated chronic diseases suggest a potential benefits of the use of Nrf2 activator to protect against age-associated oxidative damage as well as increase the lifespan[6][2][1].
- ^ a b c Bruns, Danielle R.; Drake, Joshua C.; Biela, Laurie M.; Peelor, Frederick F.; Miller, Benjamin F.; Hamilton, Karyn L. (2015). "Nrf2 Signaling and the Slowed Aging Phenotype: Evidence from Long-Lived Models". Oxidative Medicine and Cellular Longevity. 2015. doi:10.1155/2015/732596. ISSN 1942-0900. PMC 4637130. PMID 26583062.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ a b c d Liddell, Jeffrey R. (2017-08-18). "Are Astrocytes the Predominant Cell Type for Activation of Nrf2 in Aging and Neurodegeneration?". Antioxidants (Basel, Switzerland). 6 (3). doi:10.3390/antiox6030065. ISSN 2076-3921. PMC 5618093. PMID 28820437.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ a b c Gounder, Sellamuthu S.; Kannan, Sankaranarayanan; Devadoss, Dinesh; Miller, Corey J.; Whitehead, Kevin J.; Whitehead, Kevin S.; Odelberg, Shannon J.; Firpo, Matthew A.; Paine, Robert (2012). "Impaired transcriptional activity of Nrf2 in age-related myocardial oxidative stress is reversible by moderate exercise training". PloS One. 7 (9): e45697. doi:10.1371/journal.pone.0045697. ISSN 1932-6203. PMC 3454427. PMID 23029187.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ a b c Suh, Jung H.; Shenvi, Swapna V.; Dixon, Brian M.; Liu, Honglei; Jaiswal, Anil K.; Liu, Rui-Ming; Hagen, Tory M. (2004-03-09). "Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid". Proceedings of the National Academy of Sciences of the United States of America. 101 (10): 3381–3386. doi:10.1073/pnas.0400282101. ISSN 0027-8424. PMID 14985508.
- ^ a b c Safdar, Adeel; deBeer, Justin; Tarnopolsky, Mark A. (2010-11-30). "Dysfunctional Nrf2-Keap1 redox signaling in skeletal muscle of the sedentary old". Free Radical Biology & Medicine. 49 (10): 1487–1493. doi:10.1016/j.freeradbiomed.2010.08.010. ISSN 1873-4596. PMID 20708680.
- ^ Zhang, Hongqiao; Davies, Kelvin J. A.; Forman, Henry Jay (November 2015). "Oxidative stress response and Nrf2 signaling in aging". Free Radical Biology & Medicine. 88 (Pt B): 314–336. doi:10.1016/j.freeradbiomed.2015.05.036. ISSN 1873-4596. PMC 4628850. PMID 26066302.
{{cite journal}}: CS1 maint: PMC format (link)