July/August  2004

The Zen of Science

Hormesis: The middle way of stress

By Marc Ringel, MD

Much of medical language is derived from Greek and Latin, which can be pretty dense to an English speaker. The upside of these classical languages is that they construct many words with roots, prefixes and suffixes, meaning there are not so many words to learn because you can make new ones by combining the ones you already have. I call one very handy set of Greek language bits "The Three Bears," hyper-, hypo- and eu-. If the porridge is too hot, it's hyper-hot; too cold, hypo-hot; and just right, eu-hot. With respect to thyroid hormone, for example, you can have too much, making you hyperthyroid; too little, hypothyroid; or just enough, euthyroid. Likewise for blood pressure, serum sodium level and just about anything else a doctor could measure; the assessed property can be high, low or where it ought to be.

There is even an ideal range for stress. Too little stress can be as bad for you as is too much. Doctors call the right amount "eustress." Over the last half-century or so evidence has accumulated about the physiological and biochemical processes that actually enhance fitness in response to reasonable levels of stress.

Eustress is not such a strange idea. Think about exercise. Everybody understands that it takes the stress of exercise to build muscle and cardiovascular fitness. We all know lots of folks who don't get enough exercise to obtain optimum health status, plus a smaller group who compromise their health by overtraining or overworking. One of the most important services a coach can provide to an athlete is to guide her to expose herself to just the right amount of physical stress.

Alcohol is another example of the need to get the dose right. On average, teetotalers do not live as long as moderate drinkers. Of course, those who hyper-imbibe are likely to pickle their liver, brain and heart, and really shorten their life. But at moderate doses alcohol, a mild poison, presents just the sort of low level stress that improves health.

The scientific name for a process that increases organism robustness through stress is "hormesis." "Hormesis" comes from the Greek verb "hormo," meaning "I excite;" "-esis" means process. Put it together and "hormesis" means "the process of stimulating." Many of those stimulants may be toxins.

Some of the first work that was done on hormesis involved exposing bacterial cultures to radioactivity. Researchers found that there was an ideal, low-level dose of radiation that best promoted the longevity of bacteria on a culture plate. Colonies that received no radiation at all did not live as long as those that got just the right dose of ionizing energy.

Beginning in the 1960s, studies performed on higher animals established that low levels of radiation exposure can improve growth, hearing, vision, learning, memory, fertility, lifespan, and even cancer mortality. Similar results have been generated with many other stresses, including some toxins, heat exposure, and hypergravity (obtained in a centrifuge). In study after study, in a wide range of organisms, scientists uncovered a hormetic dose for different types of stress.

The biochemistry of hormesis is just being elucidated. Multiple repair mechanisms appear to get stronger when called on to fix low levels of damage to genetic and structural cell components.

Aristotle, who lived about 2,300 years ago, spoke of the " Middle Way ," the path that a prudent man [sic-critiques of sexist language weren't to arise until about 2,300 years later] should take through life. Absolutes were to be avoided. "Everything in moderation" is the one-liner that encapsulates Aristotle's ethical concept.

The Middle Way , when applied to physiology, results in the concept of hormesis or eustress. Rather than revert to my role as nagging physician and give you a list of all the things you ought to do in moderation, I'd prefer to discuss the ecological implications of the Middle Way of hormesis.

The health of forests depends on hormetic doses of wildfires. Without regular conflagrations a forest becomes choked with brush and old growth, threatening the ecological niches of all sorts of flora and fauna, thereby reducing diversity and diminishing overall robustness of the ecosystem. The hugely destructive wildfires that we've experienced in the West several summers in a row have resulted from successful firefighting, which has reduced pyro-stress below hormetic levels.

Among animals, loss of predator stress can result in environmental destruction when too many animals crowd an area, and it can result in weakened animals. One look at the sickened elk herd that spills over from Rocky Mountain National Park onto the lawns of Estes Park will convince you of the loss of population control and vigor that has resulted from near elimination by humans of elk predators: Wolves, bobcats, bears, and coyotes. Elk herds and ecosystems that support them depend on carnivores for their health.

Let's jump now to human populations. Is the Environmental Protection Agency really doing us a favor by setting zero tolerance limits for some pollutants? Hormesis says that stressors, chemical or otherwise, do not usually generate a linear dose-response curve, with risk tending to zero as dosage does. The standard graph of toxin exposure follows the hormetic u-shape, with lowest rates of death above zero concentration. Robustness diminishes both above and below the nonzero minimum.

The implication for environmental science and toxicology is clear. Scientists must seek out the minimum point on the dose-response graph and set that point as the goal for environmental exposure, not zero. The wonderful bonus of such an approach is that wringing the last few parts per million or billion of a toxin out of a water supply, for example, is way more expensive than wringing out the preceding gazillion molecules because the more dilute a solution, the harder it is to extract the solute. Allowing target pollutants to be present at extremely low but reasonable, hormetic levels would free up all sorts of money to study a larger portion of the hundreds of thousands of potentially harmful chemicals, natural and industrial, that we encounter in our environment.

Here's another argument for the Middle Way . We now know (sorry, Mom) that there is such a thing as too clean. Research has demonstrated, conclusively, that children who are exposed to too little dirt are more likely to carry allergies into adulthood. Well-done scientific studies have shown that one of the best ways to reduce kids' risk of developing hay fever, eczema or asthma is to bring pets into the house, with all their attendant schmutz. It seems that if a developing immune system does not get enough antigens to practice on (that is, antigenic eustress) the organism will be less good at deciding which substances can cause real harm and be more likely to make itself sick with allergic reactions to benign allergens, such as dust mites or ragweed pollen.

My wife even has a hormetic theory to explain young people's current obsession with body piercing and tattoos. She believes that, in the name of public health and lawsuits, we have made playgrounds too safe. Without the beloved metal and wood merry-go-rounds, teeter-totters and slides that so regularly produced scrapes and bruises-and occasional broken bones-among us and our cohorts, our kids receive an insufficient dose of minor injuries. Consequently, as adolescents and young adults they are choosing to do more painful things to themselves because that's how humans are built. Just as forests depend for their health on wildfires, elks on wolves, and immune systems on dirt, kids depend on a certain low level of injury.

      I wonder how Aristotle would react to seeing his Middle Way lead in such kinky directions. I trust it wouldn't make him too hyper-.