Concept: The Role of Hormesis in Whole Person Health

Project Concept Review

Council Approval: March 4, 2025

Program Director: Sekai Chideya-Chihota, M.D., M.P.H.

Background

Hormesis is commonly defined as a biphasic dose response where low doses of a substance or activity are stimulatory while higher doses are inhibitory. The literature contains hundreds if not thousands of examples across a wide array of biological systems and interventions. Well-known examples include the impact of caloric restriction or exercise on longevity. In both cases, small doses of the intervention are associated with increases in longevity. However, the benefits typically plateau at around 30 to 60 percent improvement and then trend in the other direction at higher doses until a threshold is crossed where increasing doses become detrimental to health.

Beyond the technical details that define hormesis, there is a general lack of understanding about the implications of this phenomenon for health. We’ve all heard the adages, “what doesn’t kill you makes you stronger,” and “too much of a good thing can be bad.” Nevertheless, which interventions exhibit this pattern, at which doses, and for which outcomes, is very poorly understood. This is due to the rigorous experimental procedures needed to properly document hormesis. To do so requires a wide range of doses, multiple replicates, variations in the duration of the exposure, and long duration of experiments. Conducting this research in a clinical setting is particularly challenging and costly under these criteria.

This concept is relevant to many complementary and integrative health interventions. One prominent example is the intersection between nutrition and dietary supplements. Most natural products are present at relatively low doses in the diet. The human body likely benefits best when exposed to those naturally existing levels. However, when sold as dietary supplements, the concentrations can be several orders of magnitude higher. Without understanding which natural products exhibit hormesis and what doses define the inflection point between helpful and harmful, it is impossible to know which supplements and which doses might be beneficial. Hormesis equally applies to mind and body interventions. Physical inputs such as spinal manipulation, saunas, and cold baths are all associated with positive health impacts. However, it’s easy to appreciate how too much of any of these could be dangerous. Less clear is how this might apply to psychological inputs such as meditation. In all cases, more research is needed to better define the dose response curve for each condition so that the “sweet spot” that maximizes benefit can be defined.

Purpose of Proposed Initiative

This initiative would support multiple lines of research around hormesis. One line would support a systematic evaluation of natural products to better define which ones exhibit hormesis. This would include medium- to high-throughput assays in multiple in vitro and in vivo platforms. The result would be a catalog of which natural products exhibit hormesis and the parameters that define the dose response for each. A second line would support research on natural products as well as mind and body interventions that attempts to leverage this phenomenon for better health. This would focus on translational efforts to understand how best to conduct this research in a clinical setting. A third line would seek to identify interventions, models, and biological outcomes that may be more easily translated than others.

Objectives

This concept is broad in its scope. Each line of research described above could conceivably be supported by one or more different funding opportunities. Examples of potential research topics include but are not limited to:

• High-throughput screening of natural product libraries in cellular systems and/or nonvertebrate models to ascertain which natural products exhibit a hormesis dose response and under which conditions.
• In vivo studies to replicate and validate existing literature showing hormesis for a range of complementary health interventions (including natural products and mind and body interventions).
• Research on various complementary and integrative health interventions in higher order animal models to develop, refine, and optimize the experimental conditions to maximize the hormesis response.
• Efforts to define and optimize research methods to improve the practicality of future clinical trials on hormesis.