Hormesis defined

Abstract

Hormesis is a term used by toxicologists to refer to a biphasic dose-response to an environmental agent characterized by a low dose stimulation or beneficial effect and a high dose inhibitory or toxic effect. In the fields of biology and medicine hormesis is defined as an adaptive response of cells and organisms to a moderate (usually intermittent) stress. Examples include ischemic preconditioning, exercise, dietary energy restriction and exposures to low doses of certain phytochemicals. Recent findings have elucidated the cellular signaling pathways and molecular mechanisms that mediate hormetic responses which typically involve enzymes such as kinases and deacetylases, and transcription factors such as Nrf-2 and NF-kappaB. As a result, cells increase their production of cytoprotective and restorative proteins including growth factors, phase 2 and antioxidant enzymes, and protein chaperones. A better understanding of hormesis mechanisms at the cellular and molecular levels is leading to and to novel approaches for the prevention and treatment of many different diseases.

Figure 1

Biphasic dose-response effect of the lipid mediator ceramide on nerve cells. Cultured rat hippocampal neurons were either pretreated for 20 h with the indicated concentrations of ceramide and then exposed to 10 uM of the excitatory amino acid neurotransmitter glutamate for 24 h, or were exposed to vehicle (control) or increasing concentrations of ceramide alone. Neuronal survival was then quantified. Modified from Goodman and Mattson (1996).

Figure 2

The cellular and molecular information flow that mediates hormesis in organisms and cells. Hormesis can be initiated by exposure of organisms to extrinsic stimuli such as exercise, dietary modifications and environmental factors including heat and low doses of toxins. In addition, cellular hormesis can be induced by activation of intrinsic signaling pathways by (for example) changes in energy availability, hormones and neurotransmitters. Such hormetic exposures typically result in mild cellular stress involving free radical production, ion fluxes and increased energy demand. In response, adaptive stress response pathways involving kinases and deacetylases (for example) and transcription factors are activated in cells resulting in the production of hormetic effector proteins that protect cells against more severe stress. Examples of such stress resistance proteins include antioxidants, protein chaperones, growth factors, and proteins involved in the regulation of energy metabolism and cellular calcium homeostasis.

Figure 3

Model for the involvement of hormesis in the beneficial effects of lifestyle, diet and drugs on health.