CHEMICAL AND BIOLOGICAL INVESTIGATION OF KEAP1–NRF2 PATHWAY AND ROLE OF SESAMIN IN OXIDATIVE STRESS AND AGEING

Abstract

The Kelch-like ECH-associated protein 1 and nuclear factor erythroid 2-related factor 2 (KEAP1–NRF2) signalling axis is the most critical and conserved cellular defence system against redox perturbations. Under basal conditions, NRF2 is constitutively ubiquitinated and targeted for proteasomal degradation through its interaction with KEAP1, a Cullin 3 based E3 ubiquitin ligase adaptor. Upon exposure to oxidative or electrophilic stimuli, cysteine residues within KEAP1 are covalently modified, disrupting its interaction with NRF2. Consequently, NRF2 escapes proteasomal degradation, translocate to the nucleus, and heterodimerizes with small musculoaponeurotic fibrosarcoma (sMAF) proteins to drive transcription of antioxidant response element (ARE)-dependent cytoprotective genes. Sesamin, a lipophilic lignan abundantly present in sesame seeds (Sesamum indicum), has emerged as a biologically significant natural compound with well documented antioxidant, anti-inflammatory, and neuroprotective properties. This activation then stimulates an increase in the amount of NRF2 transported into the nucleus, a decrease in the amount of KEAP1 in cells, and an increase in the number of ARE regulated cytoprotective genes expressed by the cell. The biological significance of the NRF2 pathway extends to multiple organ systems. With age, there is a decline in NRF2 activity resulting in the accelerated pace of cellular senescence, development of the senescence-associated secretory phenotype (SASP), neurodegeneration, sarcopenia, impaired lacrimal and salivary gland functioning, and hearing loss. Data from both in vitro and in vivo experimental settings establish that treating rats or providing a diet that includes components proven to restore NRF2 activity can lessen some of the effects associated with advanced age. Because of sesamin’s demonstrated ability to modulate NRF2, it is an attractive candidate for developing a natural therapeutic approach to counteract the effects of aging due to oxidative stress and neurodegeneration. This dissertation incorporates redox chemistry, molecular biology, and natural product pharmacology to present a complete view of the KEAP1–NRF2–sesamin axis and its role in maintaining healthy ageing.