Figure 1. Stress responses are normal reactions to the demands of life. (A) The myriads of physicochemical parameters that characterize an organism fluctuate constantly around an optimum. The intensity and duration of fluctuation may vary for different parameters; yet by the combined action of their respective sensors (mostly transcription factors) these values tend to remain (at least while young) within a physiological range (zone of homeodynamics). The zone of stress in a medical or biological context is defined as a physical or mental condition that causes tension. Stress is caused by either molecules that exceed a physiological concentration (e.g. ROS) or by external (e.g. UV, pollutants, drugs, etc) stressors. Stress responses launch specific genomic alterations that readjust the cellular proteostatic and metabolic networks in order to normalize non-physiological values and/or neutralize external stressors. (B) Stress-mediated Nrf2 activation triggers (among others) an adaptive metabolic response which by suppressing (as part of a negative feedback loop) the InS/GF axis indirectly reallocates resources from growth and longevity to somatic preservation and stress tolerance . In the young organism Nrf2 activation gradually relieves stress; yet, for the circuit to close this process has to be tightly linked with parallel Nrf2 inactivation. The latter is ensured by evolutionary favored build-in negative feedback loops that in the case of Nrf2 trigger both its functional inactivation (e.g. by Gsk3) and/or its physical elimination (e.g. Keap1-mediated degradation) ; explaining thus, why Nrf2 (and most other stress sensors) is a short-lived protein with low basal levels (⭢ denotes positive regulation and ┤a negative regulatory effect).