Transcriptional mediators of cellular hormesis

Hormesis is the beneficial adaptive response of cells and organisms to acute subtoxic doses of certain types of environmental stressors (e.g., heat, oxidation, environmental toxins). Repetitive hormesis through routine exercise, calorie restriction, or ingestion of low levels of phytotoxins with the diet can stimulate cellular catabolic turnover of damaged molecules and increase protective mechanisms. The net result is an improved ability of the organism to better cope with noxious insults (i.e., preconditioning). Key to the benefits of hormesis are (1) the intensity of the stress/toxin, which needs to be enough to stimulate an effective response without causing permanent damage (i.e., subtoxic) and (2) the duration of the exposure, which needs to be limited (acute) to allow repair and recovery. Fundamental to the hormetic adaptive response is gene expression regulation. Although different stressors elicit unique signature responses, the comparison of prototypical hormetic inducers has highlighted the role played by a few transcription factor families. The periodic pulsatile activation of Nrf2, NF-κB, HSF, and FOXO has been found to be essential to obtaining the beneficial effects of various hormetic stimuli in different biological models. This chapter discusses molecular mechanisms and gene targets for these transcription factor families in the hormetic adaptive context.