How does hormesis impact biology, toxicology, and medicine?

Abstract

Hormesis refers to adaptive responses of biological systems to moderate environmental or self-imposed challenges through which the system improves its functionality and/or tolerance to more severe challenges. The past two decades have witnessed an expanding recognition of the concept of hormesis, elucidation of its evolutionary foundations, and underlying cellular and molecular mechanisms, and practical applications to improve quality of life. To better inform future basic and applied research, we organized and re-evaluated recent hormesis-related findings with the intent of incorporating new knowledge of biological mechanisms, and providing fundamental insights into the biological, biomedical and risk assessment implications of hormesis. As the literature on hormesis is expanding rapidly into new areas of basic and applied research, it is important to provide refined conceptualization of hormesis to aid in designing and interpreting future studies. Here, we establish a working compartmentalization of hormesis into ten categories that provide an integrated understanding of the biological meaning and applications of hormesis.

Fig. 1

Evolutionary hormesis-based adaptations that enabled organisms to survive and flourish in the presence of toxic metals. The solubilization of iron and copper in rocks results in the formation of ions (Fe²⁺ and Cu⁺) that can be highly toxic to cells. During respiration (oxidative phosphorylation), cells generate hydrogen peroxide (H₂O₂). Interaction of H₂O₂ with Fe²⁺ or Cu⁺ results in the generation of the highly destructive hydroxyl free radical (OH^−.), which can kill cells by damaging DNA, proteins, and membrane lipids. Beginning very early in the evolution of life, organisms evolved proteins to protect themselves against Fe²⁺ or Cu⁺ toxicity. The proteins include those that sequester the metal ions or expel them from the cell. In addition, various iron- or copper-dependent enzymes evolved that used the redox properties of these elements to their advantage. Examples of proteins involved in iron and copper metabolism are shown. FRO7 ferric chelate reductase oxidase 7; P1C1 permease in chloroplasts; PAM peptidylglycine-alpha-amidating monooxygenase; V1T1 vacuolar iron transporter 1. All images in the figure were obtained from Wikimedia Commons under the Creative Commons copyright 4.0 International, 2.0 Generic, and Share Alike 2.5 Generic (CC-BY) license, and GNU Free Documentation 1.2 license

Fig. 2

Responses to hormetic challenges are coordinated across multiple organ systems, and involve both cell autonomous molecular mechanisms, and signals transmitted between different tissues. Exercise and fasting impose bioenergetic challenges to multiple organ systems, with responses of muscle, nerve cell networks, liver, and adipose cells being particularly important during the exercise. A major source of exposures to potentially toxic agents is their ingestion as components of food and water, or as man-made drugs. Numerous signaling molecules are released into the blood in response to environmental challenges, and function to coordinate hormetic responses of various organ systems. The brain plays major roles in adaptive responses to a wide range of hormetic exposures, mediating both immediate responses, and enduring changes in synaptic connectivity, and learning and memory, that optimize performance under challenging environmental conditions. (for in-depth discussion see refs. 36, 41, 77). Images for Digestive Tract and Capillaries from Wikimedia Commons under the Creative Commons copyright (CC-BY-SA) 2.5 license, other images in Fig. 2 were created by author M Mattson and have not been previously published

Fig. 3

Distribution of predicted mean response and 95% prediction interval values of the 253 chemicals satisfying the a priori entry criteria for the wild-type strain with three responses below the BMD₅. These findings are compared to expectations for a threshold model (Source: ref. 28).