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

Area of Science:

• Gerontology and Molecular Biology
• Cellular Stress Response Mechanisms

Background:

• Oxidative stress, an imbalance between oxidants and antioxidants, disrupts cellular redox signaling and causes molecular damage, implicating it in aging and senescence-related diseases.
• The Kelch-like ECH-associated protein 1- (Keap1-) nuclear factor-erythroid 2-related factor 2 (Nrf2) system is a key regulator of antioxidant responses and is closely linked to the aging process.
• Keap1-Nrf2 signaling is modulated by complex networks, including PI3K/Akt, protein kinase C, and MAPK pathways.

Purpose of the Study:

• To review molecular mechanisms underlying aging processes involving the Keap1-Nrf2 system.
• To highlight key signaling pathways and molecular events that regulate Nrf2 unbinding from Keap1.
• To discuss the interaction between the Keap1-Nrf2 system and the mTOR pathway in the context of aging.

Main Methods:

• Literature review focusing on aging-related molecular mechanisms.
• Analysis of signaling pathways modulating Keap1-Nrf2 interactions.
• Discussion of molecular signals influencing Nrf2 dissociation from Keap1.

Main Results:

• Identified cysteine modification of Keap1 and phosphorylation of Nrf2 as critical signals for Nrf2 unbinding.
• Highlighted the roles of PI3K/Akt/GSK3β, sequestosome 1, Bach1, and c-Myc in modulating Keap1-Nrf2 activity.
• Detailed the direct interaction between the Keap1-Nrf2 pathway and the mammalian target of rapamycin (mTOR) pathway.

Conclusions:

• The Keap1-Nrf2 system is a central player in oxidative stress and aging.
• Understanding the regulatory network of Keap1-Nrf2 provides insights into aging mechanisms.
• This research offers an empirical foundation for developing novel antiaging therapeutics targeting the Keap1-Nrf2 pathway.