We’ve all heard the phrase, “What doesn’t kill you makes you stronger.” In a certain sense, it turns out, that’s actually true. Renaissance physician and philosopher Paracelsus famously said, “All things are poison and nothing is without poison, only the dose permits something not to be poisonous.”
Examples include critically important minerals in the body like iron, selenium, and iodine. A small amount of these are necessary for life and optimal functioning, but too much can be dangerous, or even deadly. Carbon monoxide is another example: it irreversibly binds to hemoglobin, preventing its ability to bind oxygen and resulting in asphyxiation… but in small doses, it serves as a signaling molecule in nerve cells.
The idea is broader than just substances, though. Exercise is a type of hormetic stressor: microtears in the muscles cause them to actually grow during the repair process. Fasting is a big one: calorie restriction leads to autophagy, allowing the body to clean up damaged cells and produce new, healthy ones instead. Contrast bathing operates by similar principles.
In toxicology, this concept is known as hormesis: the idea that small exposures to a toxin can have a beneficial effect upon an organism, while larger doses do act as poison. In fact, many of the modalities used in naturopathic medicine rely upon this principle: the idea that a minor (and usually short-lived) stressor will result in a compensatory and opposite response in the body, in order for it to maintain homeostasis.
Antioxidants: Beneficial or Harmful?
For decades, oxidative stress was the reigning theory of the cause of aging. Indeed, oxidative stress has been linked to most chronic diseases, and it is undoubtedly quite toxic when in excess.
However, the majority of oxidative stress in the body comes from the mitochondria themselves. Healthy mitochondria have very little “leakage” into the surrounding cell, but at least 4-5% of the oxygen that goes in does leak out, turning into free radicals like hydroxyl (OH-), superoxide anion (O2-), hydrogen peroxide (H2O2), hypochlorite (OCI-), and peroxynitrite (ONOO-). While the body uses antioxidants such as glutathione to clean this up, small amounts of oxidative stress are also part of the mitochondrial feedback mechanisms, signaling that the body has lower need for energy. This helps the mitochondria to adapt to the needs of the moment, while the oxidative stress itself triggers increased production of antioxidants and enzymes for detoxification.
This may be the reason why studies of high-dose antioxidants haven’t been nearly as impressive as we once expected them to be. Some antioxidants are good, but excessive amounts don’t seem to be better.
(Feedback mechanisms of all kind are like this, allowing the body and the individual to learn how to respond to the world around them. Pain, when functioning properly, serves this purpose, sending signals like, “Don’t touch that hot stove!”)
Phytochemicals (Plant Toxins)
Many of our favorite medicinal plant compounds are actually toxins the plant produces to ward off insects. Considering the body weight dose an insect might get compared to us, it might explain our different physiological response.
Some of these compounds include:
- caffeine (and coffee incidentally can also be helpful or harmful to us too, in a dose-dependent way)
- curcumin, which is not a direct but a hormetic antioxidant, in the sense that it triggers the body to produce them
- resveratrol, shown to stimulate the longevity enzymes sirtuins (more on this below)
- sulforaphane, which also stimulates antioxidant production
- capsaicin, the “burning” compound in peppers paradoxically used topically to quell pain
- allicin, the antimicrobial compound primary in garlic and onions.
Mental Stress and Neuroplasticity
Aging adults at risk for dementia are often encouraged to engage in mental exercises. This seems to make intuitive sense, if we consider how physical exercise works. It certainly does appear that the effort pays off for hormetic reasons.
The NMDA receptors on the neurons, involved in learning and memory, trigger the influx of calcium. Because at the core, all of these activities involve mitochondria, just the act of using these pathways triggers production of some free radicals.
Fasting and Intermittent Fasting
As mentioned in the introduction, fasting enables the body to spend the energy it might otherwise expend upon digestion and instead “clean house,” eliminating damaged cells and instead producing new ones, in a process called autophagy. Part of the reason it does this is because fasting activates the enzyme AMP-activated protein kinase (AMPK), which in turn triggers autophagy.
At the same time, fasting also lowers both insulin, and insulin-like growth factor 1 (IGF-1). The latter inhibits autophagy, so this is another mechanism by which fasting promotes it.
Exercise and Longevity
Weight-bearing exercise causes muscle growth through initial damage, a hormetic process. However, both weight bearing and aerobic exercise increase increase NAD, which in turn is a cofactor needed to activate the anti-aging enzymes called sirtuins. These also promote autophagy.
Cross-Benefits of Hormetic Stressors
The good news is, exposure to one kind of hormetic stressor seems to confer protection against another, as well. Heat stress, for instance, can protect those same cells against oxidative or toxic stress later. (Hormesis may be at least in part why sauna bathing is associated with lower all-cause mortality.)
Another example: exposure to low doses of a mitochondrial toxin protects those same cells from later death by ischemia, or lack of oxygen.
Traditional pharmaceuticals in most cases work against this principle. They are strong enough to exert a primary, rather than a secondary effect, inevitably leading to compensatory mechanisms elsewhere (aka side effects). But small doses of those same drugs might be expected to have a very different effect.
The dose determines whether a substance (or an activity) is medicine or poison.