Nrf2 as a Point of Intervention for Cellular Stress Responses
Upregulation of various forms of cellular stress response has been shown to modestly slow aging in a variety of short-lived laboratory species. Allowing cells to better maintain a healthy state in response to stresses such as heat or low nutrient availability reduces the pace at which age-related damage accumulates to cause dysfunction. This improvement in stress responses is a portion of the calorie restriction response, and thus unlikely to produce effects on life span that are as large in longer-lived species. Nonetheless, it is the subject of a great deal of research. Scientists here discuss the role of Nrf2 in the mechanisms by which some supplements and dietary compounds can provoke greater levels of cellular stress responses. Nrf2, and mechanisms regulating the amount of Nrf2 present in cells, are possible targets for approaches designed to enhance cellular stress responses to a greater degree than is possible via supplement-like strategies.
The cellular stress response is regulated at the transcriptional, translational, and post-translational levels by a family of heat shock transcription factors (HSFs) that are expressed and maintained in an inactive state under non-stress conditions. HSFs, essential for all organisms to survive to acute or chronic stress, are also important for normal development and lifespan-enhancing pathways, and the repertoire of HSF targets has thus expanded well beyond the heat shock genes.
Post-translational regulation of HSFs is emerging to integrate the metabolic state of the cell with stress biology, whereby controlling fundamental aspects of the health of the proteome and aging. In addition to this, the KEAP1/Nrf2/ARE pathway is the basis of the cellular defense. Induction of this pathway has been shown to be protective against various stress conditions. On the other side, under conditions of Nrf2 deficiency with failure to upregulate this pathway, increased sensitization and accelerated disease pathogenesis have been demonstrated.
Transcription factor Nrf2, under basal conditions, is continuously targeted for ubiquitination and proteasomal degradation by KEAP1, a protein acting as a repressor. It is well defined now that many inducers of the Nrf2 pathway chemically modify specific cysteine residues within KEAP1, leading to the loss of its ability to target Nrf2 for degradation. Subsequently, Nrf2 levels accumulate and hence activate transcription of NRF2-dependent genes which encode a large network of cytoprotective proteins, including those that are involved in the metabolism and transport of a wide array of endobiotics and xenobiotics, proteins that have antioxidant functions, as well as those that participate in the synthesis, utilization, and regeneration of glutathione and NAD(P).
Several phytochemicals act through the activation of transcription factor Nrf2. Under basal conditions, these protective systems do not operate at maximum capacity but can be induced to higher activity levels by redox-active compounds, such as hormetic nutrients, thus reducing the risks of developing malignancies and multiple chronic diseases.