Lability of the Nrf2/Keap/ARE Cell Defense System in Different Models of Cell Aging and Age-Related Pathologies

The level of oxidative stress in an organism increases with age. Accumulation of damages resulting in the disruption of genome integrity can be the cause of many age-related diseases and appearance of phenotypic and physiological signs of aging. In this regard, the Nrf2 system, which regulates expression of numerous enzymes responsible for the antioxidant defense and detoxification, is of great interest. This review summarizes and analyzes the data on the age-related changes in the Nrf2 system in vivo and in vitro in various organs and tissues. Analysis of published data suggests that the capacity for Nrf2 activation (triggered by the increased level of oxidative stress) steadily declines with age. At the same time, changes in the Nrf2 activity under the stress-free conditions do not have such unambiguous directionality; in many studies, these changes were statistically insignificant, although it is commonly accepted that the level of oxidative stress steadily increases with aging. This review examines the role of cell regulatory systems limiting the ability of Nrf2 to respond to oxidative stress. Senescent cells are extremely susceptible to the oxidative damage due to the impaired Nrf2 signaling. Activation of the Nrf2 pathway is a promising target for new pharmacological or genetic therapeutic strategies. Suppressors of the Nrf2 expression, such as Keap1, GSK3, c-Myc, and Bach1, may contribute to the age-related impairments in the induction of Nrf2-regulated antioxidant genes. Understanding the mechanisms of regulatory cascades linking the programs responsible for the maintenance of homeostasis and cell response to the oxidative stress will contribute to the elucidation of molecular mechanisms underlying aging and longevity.