Human age-related cataracts: Epigenetic suppression of the nuclear factor erythroid 2-related factor 2-mediated antioxidant system

Human aging is a multifactorial process. The most prominent effects of aging include visual impairments, particularly age-related cataracts (ARC). Several studies have reported that oxidative stress and failure of the antioxidant system are the major factors contributing to lens oxidation.. The present study focused on the nuclear factor erythroid 2-related factor 2 (Nrf2)/kelch-like ECH-associated protein 1 (Keap1)-mediated antioxidant system and its failure in aging lenses. The protein levels, gene expression and methylation status of Nrf2/Keap1 were investigated in human lenses from different age groups. Human lens epithelial cells were collected from different age groups ranging between 15 and 80 years and cataract lenses were also collected for the comparative study. The results demonstrated significantly lower protein and gene expression levels of Nrf2 in lenses of increasing age; however, a significant increase in the expression of the Nrf2 regulator, Keap1, was observed. Based on these results, the present study then aimed to investigate the underlying mechanisms. A gene specific DNA methylation study was performed in cataractous lenses of different ages, which revealed significantly increased levels of demethylated DNA in the Keap1 promoter with increasing age. Notably, the results from cataract lenses demonstrated significant demethylation of the Keapl promoter, which was also reflected in the results of clear lenses aged between 66 and 80 years. These results suggested that demethylation in the Keap1 promoter region activated the expression of the Keapl, protein, which then increased the targeting of Nrf2 for proteasomal degradation. Therefore, decreased activity of Nrf2 restrained the transcription of its downstream antioxidant enzyme and led to the failure of the antioxidant system, ultimately leading to the formation of ARCs.