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Role of Nrf2 in aging:
Nrf2 signaling and its function is altered with age which is believed to be responsible for aging phenotype. 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. The data on this matter various depending on in which cells and tissues the nrf2 activity has been studied.

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. The results show a significant decrease of Nrf2-ARE signaling in the aging heart. 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. Another study looked at the Nrf2 activity in aging liver of rats and examined the Nrf2 activity at cellular and nuclear levels. The analysis demonstrated a decline in hepatic Nrf2 levels in old rats at both cellular and nuclear levels when compared to young rats. This indicates that aging has an adverse effect on basal Nrf2-mediated gene transcription. 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. Altered regulation of Nrf2/Keap1 redox signaling was noted in the skeletal muscle tissue of the sedentary old group. Moreover, when comparing the Nrf2 protein contents among the three groups, the active old group showed a significant higher contents than the other groups.

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.