Hormesis and Xenohormesis –
Potential Health Benefits

By Paul E. Lemanski, MD, MS, FACP

Editor’s Note: This is the 124th in a series on optimal diet and lifestyle to help prevent and treat disease. Any planned change in diet, exercise or treatment should be discussed with and approved by your personal physician before implementation. The help of a registered dietitian in the implementation of dietary changes is strongly recommended.

Medicines are a mainstay of American life and the healthcare system not only because they are perceived to work by the individuals taking them, but also because their benefit may be shown by the objective assessment of scientific study. Clinical research trials have shown that some of the medicines of Western science may reduce the risk of Type 2 diabetes, heart attacks, strokes, cardiovascular death and even some cancers.

In the previous installments of the Non-Medicated Life, a healthy diet and lifestyle have been shown to accomplish naturally for many individuals most of the benefits of medications in the prevention of the chronic medical conditions mentioned above. With respect to a healthy lifestyle and diet this column has suggested that moderate aerobic exercise and resistance training, the restriction of calories to maintain a normal body weight, and a predominantly whole foods, plant-based diet together produce health benefits. The mechanism of the health benefits may involve an adaptation to stress called hormesis or more simply: what doesn't kill us makes us stronger.

Hormesis is a biphasic dose–response phenomenon: a low dose of a stressor produces a beneficial, adaptive effect, while a high dose of the same agent causes harm. In toxicology, where the term originated, this appears as a characteristic inverted-U or J-shaped curve, with a threshold – the “zero equivalent point” – below which the stressor stimulates rather than inhibits. 

In medicine and biology, hormesis is defined more broadly as an adaptive response of cells and organisms to a moderate, usually intermittent stress. This principle may seem counter-intuitive. We tend to assume that if something is toxic at a high dose, it is proportionally harmful at every dose. Biology, however, violates this assumption.

Small, well-timed challenges – a hard workout, a hot sauna, fasting, a modest dose of a plant toxin – activate ancient stress-response circuitry that leaves the organism more resilient than before. The adaptation, not the stress itself, is the benefit.

Hormetic responses involve a small set of highly conserved signaling networks. For example, mild oxidative stress oxidizes cysteine residues on the Keap1 protein, releasing the transcription factor Nrf2, which translocates to the nucleus and binds antioxidant response elements, inducing expression of more than 500 cytoprotective genes – including superoxide dismutase, glutathione peroxidase, and phase-2 detoxifying enzymes. Parallel pathways of the response include activation of the sirtuins, FOXO transcription factors, heat-shock proteins, and NF-κB; together the activation of these pathways up-regulates antioxidant defenses, DNA repair, and autophagy (the consumption of defective proteins and cell structure) leading to improved function and resilience in the face of similar stressors.

Two features of the hormetic response deserve emphasis. First, the magnitude of the stressor is typically modest – roughly 30-60% above the baseline level. Any greater stress and and damage predominates rather than adaptation and improved function. Second, hormesis requires a period of recovery; the stressor must be intermittent, followed by rest, for the adaptation to lead to improved function.

The best evidence for the benefits of hormetic intervention in humans is ordinary exercise. Muscular contraction generates reactive oxygen species, depletes glycogen, and disrupts homeostasis – and in response, cells up-regulate mitochondrial bio-genesis, antioxidant enzymes, neurotrophic factors, and stress-resistance proteins. The health benefits of regular, moderate exercise are improved cardio-respiratory fitness, delayed metabolic disease, enhanced cognitive function, and statistically significant lower all-cause mortality.

Examples of hormesis are also found with other practices now supported by mechanistic and, to varying degrees, clinical evidence: the stress of intermittent fasting improves metabolic health; the stress of modest dietary caloric restriction (activating sirtuins and FOXO) extends lifespan in multiple species; the stress of modest heat exposure (inducing heat-shock proteins) in a sauna can improve blood pressure, immune function, and stroke risk; the stress of cold exposure in an ice bath (catecholamine release, vascular adaptation) can improve systemic inflammation and possibly reduce anxiety.

Hormesis, interestingly, is not confined to animal species and humans. It is also seen in plants. Plants cannot flee stressors, so when challenged by drought, salinity, UV radiation, heat, cold, or pathogen attack, they mount a chemical defense by synthesizing secondary metabolites – polyphenols, flavonoids, glucosinolates, phytoalexins, carotids – that protect the plant from the stressor. For example, broccoli and broccoli sprouts cultivated under the stress of increased soil salt content show increased production of glucoraphanin and sulforaphane, substances which allow biochemical adaptation and survival. In a similar manner, conditions of drought raise glucosinolates and carotenoids in broccoli, again allowing adaptation to adverse conditions and survival.

Interestingly, this biochemical adaptation of plants to adverse conditions allowing survival produces many of the same substances used by animal cells to adapt to stress. As a result, consuming plants that have been stressed under adverse conditions may improve the adaptation of animal cells to stress. The xenohormetic hypothesis, coined by Howitz and Sinclair, explains why consuming these compounds benefits us. When a plant ramps up its defenses, it signals deteriorating environmental conditions; animals that consume the plant then preemptively up-regulate their own stress-resistance pathways and thereby gain a survival advantage.

In this view, many beneficial phytochemicals are not “antioxidants” in the strict sense; their concentrations in plasma after dietary intake are far too low to scavenge free radicals effectively. Rather, they are mild pro-oxidant stressors that activate Nrf2 and other pathways, prompting the body to build its own antioxidant capacity. Sulforaphane from broccoli is the best studied example: when the plant is chewed the glucosinolate glucoraphanin is converted by the plant’s myrosinase to sulforaphane, giving the plant a bitter taste and protecting it from further animal consumption; additionally, sulforaphane is a potent Nrf2 activator that upregulates endogenous antioxidant and phase-2 detoxification enzymes, thereby protecting the consumer of the plant from oxidative damage. Resveratrol, quercetin, curcumin, and EGCG act through similar hormetic mechanisms.

In summary, hormesis is a phenomenon of mild stress that can be shown to induce adaptive responses that improve cellular function and resiliency. This adaptive response to stress requires the stressor to be mild and intermittent and include a period of rest for optimal adaptation to occur.

Practical considerations include:

• Seek mild, intermittent stress – Exercise, occasional fasting, sauna, and cold exposure are evidence-supported hormetic practices, provided they allow recovery.

• Embrace plant bitterness – The sharp taste of crucifers, the astringency of berries, the bite of extra-virgin olive oil often mark the very compounds that engage stress-response pathways.

• Consider stressed plants – Organic farming, water stress, and other preharvest challenges can raise phytochemical content – though effects vary by compound, crop, and stress severity.

• Respect the dose window – The same sulforaphane that is protective at dietary doses can be cytotoxic at the high concentrations attained through supplementation; benefits are confined to the low-dose end of the curve.

In this way hormesis and xenohormesis should be considered a valuable strategy in achieving the non-medicated life and suggest a new paradigm for optimizing health: What does not kill us, in the right dose and with the right recovery, genuinely makes us stronger.

Paul E. Lemanski, MD, MS, FACP (plemanski3@gmail.com) is a board-certified internist practicing internal medicine and lifestyle medicine in Albany, NY. Paul has a master’s degree in human nutrition, he’s an assistant clinical professor of medicine at Albany Medical College, and a fellow of the American College of Physicians.