Welcome to the Wild Side of Your Plate

Hormesis and the Power of Plants

“Bitter-tasting chemicals made by plants act as natural pesticides. When we eat plant-based foods, we consume low levels of these toxins, which mildly stresses cells in the body in much the same way that exercise or going without food for long periods does. The cells do not die—in fact, they get stronger because their response to the stress shores up their ability to adapt to still more stress. This process of bolstering cellular resilience is called hormesis—and a growing body of research indicates that it accounts for the health benefits of consuming fruits and vegetables.”
Source: Chemicals that plants make to ward off pests stimulate nerve cells in ways that may protect the brain against diseases such as Alzheimer’s and Parkinson’s. 

Dr. Mark P. Mattson's research, continues to fascinate us with findings on the true value of vegetables, emphasizing their role in triggering cellular adaptive responses that promote resilience and longevity, beyond just providing antioxidants and fiber.

Hormesis - an adaptive response that enhances the organism's ability to cope with future stress

A 150-Year-Old Concept Reborn
While the concept of hormesis might seem new, it was actually first described in the late 19th century. However, it's only in recent decades that scientists have begun to fully appreciate its implications for human health and longevity.

The Power of "Mild Stress"
We often think of stress as purely negative, something to avoid at all costs. But what if I told you that embracing certain kinds of stress could actually make you stronger? This is the fascinating concept of hormesis, where exposure to mild stressors triggers beneficial adaptive responses in our bodies.
Think of it like exercise: lifting weights puts stress on your muscles, but this stress ultimately leads to growth and increased strength. Similarly, exposing ourselves to certain types of mild stress can enhance our resilience and protect us from future harm.

Hormesis, although widely accepted, still has ongoing research and discussion regarding its mechanisms, applications, and limitations.

It is commonly defined as a biphasic dose-response phenomenon characterized by low-dose stimulation and high-dose inhibition.

This means that exposure to low doses of a stressor can result in beneficial effects (enhancing stress resistance, reducing inflammation, and promoting metabolic, immune, and cardiovascular health, even increase longevity), while higher doses can be harmful. The term "stressor" can refer to a wide range of stimuli, including physical (exercise, saunas, cold showers), chemical (phytochemicals, oxygen deprivation in high-altitude training), or biological agents (calorie restriction).
While the term "hormesis" often emphasizes the beneficial effects of mild stress, it's important to remember that the outcome of hormesis can depend on various factors and is not always positive or beneficial. Even with typically beneficial stressors, exceeding the optimal dose or applying the stressor at the wrong time can lead to negative consequences. For example, excessive exercise can lead to injuries or overtraining syndrome.

This image is adapted from Dr. Mattson's article

The effects of a stressor aren't simply proportional to its dose; instead, they follow a non-linear, biphasic pattern. This means low doses can stimulate and enhance physiological functions, promoting a positive adaptation (hormesis). However, higher doses disrupt the body's balance and can lead to harmful effects, overriding any potential benefits.

While hormesis is a fascinating concept, it's not applicable to all substances. In contrast, some substances exhibit a linear dose-response relationship, meaning any amount can contribute to harm. They can accumulate in the body over time, leading to chronic toxicity and long-term health problems. For example, arsenic demonstrates a linear dose-response, where any amount can accumulate and cause harm over time, without offering a "sweet spot" for potential benefits.

Therefore, while hormesis often highlights the positive effects of mild stress, it's essential to consider the specific context, dose, and individual factors to determine whether the outcome will be beneficial or harmful. It's not always a guarantee of positive change.

Plants and Phytochemicals

Plants are masters of hormesis, producing a variety of compounds called phytochemicals to defend themselves against pests and environmental challenges. These secondary metabolites are commonly produced in response to external stimuli like infection, nutrient availability, or changes in climate.
These hormetic phytochemicals, which trigger "just enough, not too much" responses in our bodies, are found throughout the plant kingdom. Here are some examples:

Plant source	Phytochemicals	Beneficial adaptive responses
Cruciferous vegetables (broccoli, kale, cauliflower)	Sulforaphane	Activates Nrf2 pathway, boosts antioxidant defenses, detoxification, and cellular protection.
Turmeric	Curcumin	Anti-inflammatory, antioxidant, activates various protective pathways, potential cognitive benefits.
Grapes, red wine, berries	Resveratrol	Activates sirtuins, promotes longevity, protects against age-related decline.
Green tea, cocoa	Catechins	Antioxidant, anti-inflammatory, potential cardiovascular and neuroprotective benefits.
Berries, onions, apples	Quercetin	Antioxidant, anti-inflammatory, supports immune function.
Garlic	Allicin	Cardiovascular health, immune support, potential anti-cancer properties.
Ginseng	Ginsenosides	Adaptogenic, stress response modulation, cognitive and immune benefits.
Chili peppers	Capsaicin	Pain relief, anti-inflammatory effects, potential metabolic and cardiovascular benefits.
Celery, peppers, carrots	Luteolin	Antioxidant, anti-inflammatory, potential neuroprotective and anticancer benefits.

Hormetic Pathways Triggered by Phytochemicals

Although the mechanisms of action of phytochemicals are very diverse and complex, the activation of the Nrf2 transcription factor is certainly one of the most studied. The Nrf2 pathway is a master regulator of the body's antioxidant and detoxification responses. Its activation leads to the production of protective enzymes that neutralize free radicals and detoxify harmful substances.

Different types of phytochemicals can activate Nrf2, but they may do it through different mechanisms. Sulforaphane directly activates Nrf2, wheras flavonoids (like catechins and quercetin) activate Nrf2 indirectly through various signaling pathways.

Free Radicals & Antioxidants: Striking the Right Balance
Nrf2 is a protein called a transcription factor. This means it can turn genes "on" or "off." Once activated, Nrf2 binds to specific genes and instructs them to produce special enzymes. Some of these antioxidant enzymes, like superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) participate in the neutralization of reactive oxygen species – ROS and prevent oxidative damage to cells.
On the other hand, excessive intake of synthetic antioxidants can disrupt cellular signaling and reduce the activation of Nrf2, which consequently reduces the endogenous production of antioxidant enzymes, which in the long run reduces the antioxidant protection of cells. This phenomenon is known as the "antioxidant paradox."

ROS is a broader term that includes both free radicals and non-radical oxygen-containing molecules that are oxidizing agents or can be easily converted into radicals. Reactive oxygen species are byproducts of metabolism and can cause cellular damage. However, they also act as signaling molecules, triggering adaptive responses that protect cells from future stress. Taking high doses of supplemental antioxidants can interfere with this signaling process by excessively scavenging ROS. This can prevent the activation of beneficial hormetic pathways, potentially reducing the body's natural antioxidant defenses and cellular repair mechanisms. Our bodies maintain a delicate balance of ROS production and antioxidant activity. Excessive antioxidant supplementation can disrupt this balance.
Although the antioxidant paradox is not universally accepted, it's gaining increasing recognition in the scientific community. So let's not simplify and generalize: while the antioxidant paradox raises important questions about the role of antioxidants in health, several arguments suggest that its implications may be oversimplified or misinterpreted within the broader context of oxidative stress and disease mechanisms.
In contrast there is consensus on the role of dietary antioxidants from fruits and vegetables in promoting health.

"Stressed Apples": Packed with Extra Nutrition

Simple Changes for a “Hormetic Lifestyle”

Diversify Your Diet: Don't just stick to the same old fruits and vegetables. Explore the vast array of colors, flavors, and textures that the plant kingdom offers. Each plant contains a unique profile of phytochemicals, so the more variety you consume, the wider range of hormetic benefits you'll receive.
Don't forget about other plant-based foods like nuts, seeds, legumes, and whole grains. These also contain a wealth of hormetic compounds.

Embrace the bitter and pungent flavors: These tastes often signal the presence of powerful phytochemicals that can benefit your health. Consider cruciferous vegetables like broccoli, Brussels sprouts, Chinese cabbage, turnips, watercress, and radishes, or spices like turmeric and ginger. Even the characteristic bitterness of chicory, derived from compounds like sesquiterpene lactones and inulin, can stimulate beneficial responses in your body, enhancing resilience and protecting against cellular damage.

"Lightly Toasted" Approach: Gentle cooking methods like light roasting or steaming, and fermentation, can increase the bioavailability of beneficial compounds. Lightly roasting broccoli increases available sulforaphane, while turning cabbage into sauerkraut boosts glucosinolates. Cooked tomatoes offer more lycopene, and cooked carrots deliver more beta-carotene. Avoid overcooking to preserve these benefits.

Think twice before you peel! Whenever possible, consume fruits and vegetables with their skins intact. The outer layers often contain higher concentrations of phytochemicals. Consider leaving the skins on your potatoes and cucumbers, zuccini, or even the outer layers of onions and garlic.

Spice Up Your Life: Experiment with spices like turmeric, ginger, and garlic. They not only add flavor to your meals but also provide a concentrated dose of hormetic compounds. 

Plants became food or medicine, but they could also cause nausea, vomiting or even death. Pharmacologists, toxicologists and biochemists are now confirming that plant chemicals that are toxic when consumed at high levels can be hormetic—that is, they provide health benefits when eaten in smaller amounts. Finding the precise dose or intensity of a stressor that triggers beneficial effects without causing harm is a major challenge. This "sweet spot" can vary significantly depending on the specific stressor, the individual, and various other factors.

The concept of hormesis has not escaped its share of controversy. Some researchers question whether scientists have developed adequate methods for distinguishing when a beneficial effect ends and a toxic one begins. The exact threshold for when a toxic reaction starts may vary by individual, making it difficult to use hormesis as a basis for drug therapies.

As Paracelsus, the father of toxicology, wisely stated centuries ago: "All things are poison, and nothing is without poison; only the dose makes a thing not a poison."

("Omnia sunt venena, nihil est sine veneno. Sola dosis facit venenum.")

Hormesis reminds us that growth often emerges from facing challenges, not avoiding them. So, don't simply test the limits of "what doesn't kill you," but rather seek out experiences that push you beyond your comfort zone, for they can lead to greater resilience and wisdom.



Literature:
- Neurohormetic phytochemicals in the pathogenesis of neurodegenerative diseases
- Hormetic Effects of Phytochemicals on Health and Longevity
- Phytochemical
- Current advances and future trends of hormesis in disease
- Hormetic Dietary Phytochemicals
- Hormesis determines lifespan
- The Underexplored Dimensions of Nutritional Hormesis
- Benefits and Risks of the Hormetic Effects of Dietary Isothiocyanates on Cancer Prevention
- Xenohormesis: health benefits from an eon of plant stress response evolution