Forum Building Biological Shields via Hormesis Edward J. Calabrese 1, * and Evgenios Agathokleous 2,3 Hormesis offers the potential to build biological shields to protect against a plethora of age-related diseases and acute trauma (e.g., brain traumatic injury) via the implementation of pre- and postconditioning strategies. These strategies have the potential to markedly enhance a broad spec- trum of medical and public health practices. New Approaches to Enhance Health Modern society has a high priority for enhancing overall health and well being via medical advances and public health strategies, including those of environmen- tal regulation to mitigate and minimize exposures to harmful agents. A central component of this focus is healthy aging, a process that integrates medical and public health research and practices throughout the lifespan, enhancing quality to each life stage, especially prolonging the lifespan, with multiple years of higher quality life. Novel and dynamic strategies that significantly enhance these medical, public health, and healthy aging goals need to be developed and implemented. We believe one central strategy would be to apply the evolutionary-biological con- cept of hormesis by using low doses of multiple types of stresses (e.g., pharma- cological, chemical, physical, psycholog- ical, and social) to build biological shields to protect people from subsequent threats. These threats include heart attack, stroke, neurodegenerative dis- eases, tumor development, and aging- and environment-related cellular changes mediated by protein degradation from the skin and other tissues as well as damage from various types of chemo- and radia- tion therapies and blunt force trauma from accidents and falls in organs such as the brain (Figure 1). Preconditioning Is a Manifestation of Hormesis This hormesis-biological shield strategy is based upon preconditioning, a phenom- enon in which a prior exposure to low doses of stressors induces adaptive responses that provide protection against subsequent exposures to harmful doses of the same or related agents within a time window (Figure 1). Preconditioning was first reported 90 years ago when low doses of radiation protected plants against damage from subsequent higher exposures of the same agent [1]. Over the next several decades, preconditioning was ‘re-discovered’ by different research groups in different fields and given differ- ent names (e.g., priming, adaptive response, auto-protection, acquired resistance, steeling effect, precondition- ing). These diverse terms and broad research origins lead to generally sepa- rate developments, lacking evolutionary, biological, and mechanism integration and few societal applications, including medical, public health, behavioral, social, and agricultural. Preconditioning was also impeded by the widespread idea that organisms are static entities, being victimized by environmen- tal threats such as mutagens and carci- nogens. This is clearly seen as far back as 1930, when Hermann J. Muller developed the proportionality rule, suggesting that gene mutations induced by ionizing radi- ation were unrepairable, irreversible, and cumulative, leading to the creation and widespread adoption of the linear non- threshold dose–response model that dominates governmental regulations [2]. In fact, this Muller perspective preceded the discovery of DNA repair and a pleth- ora of other adaptive responses that have constitutive and inducible components, that is, via activation of signaling path- ways and thereby gene expression and production of antioxidant enzymes, mito- chondrial proteins, protein chaperones, and a series of other components that are executed within a hormetic-biphasic context [3]. This led to the belief that lower exposure to harmful agents is always bet- ter, making zero exposure to regulated agents the expressed goal. Such per- spectives have permeated a broad spec- trum of medical and public health activities, including fear of dental X-rays, consumption of chlorinated drinking water, and a plethora of other perceived low-level threats. It also leads to the idea that carcinogenic and non-carcinogenic agents act via a type of additive to back- ground ongoing disease process under the assumption that similar exogenous and background-induced diseases occur via identical mechanisms [4]. The additive to background idea has been functionally/ mathematically incorporated into quanti- tative assessment procedures of cancer risk assessment and ensures that risks are essentially always linear at low doses, even when the experimental data are strikingly threshold and nonlinear [2]. Hormesis and Biological Shields (Conditioning) When researchers use a relatively large number of conditioning doses, the sub- sequent dose–response relationships are invariably biphasic, with the quantitative features of preconditioning effects being those of hormesis. The maximum stimu- lation/protection is less than twofold the control/background response and usually in the 30–60% range [1,5]. These hor- metic responses display considerable generality, being independent of biologi- cal model, endpoint, inducing agent, mechanism, and level of biological orga- nization, occurring at the cell, organ, and TIPS 1566 No. of Pages 3 Trends in Pharmacological Sciences, Month Year, Vol. xx, No. yy 1