The dose makes the poison…

Stress is defined “as a process of altered biochemical homeostasis produced by psychological, physiological, or environmental stressors.” Etymologically, the word is derived from Latin, meaning “tight, compressed, drawn together.” Conceptually, it can be found in the physical sciences as early as the 17th century. In physics, Hooke’s law (F = -kX)  states that the strain of an elastic object is proportional to the stress applied to it. Thereafter, in the first half of the 20th century, the endocrinologist used it to describe the biological responses to stressors.  He described the General Adaptation Syndrome as a maladaptive response to unremitting stress that leads to the secretion of stress hormones and the downstream sequelae of ulcers, high blood pressure, arteriosclerosis, arthritis, kidney disease, and allergic reactions. It entered the vernacular in the latter half of the 20th century and in the oftentimes over-reductive and oversimplified interpretations by science, medicine, and society, we presume this to mean that if chronic stress is detrimental to your health, then all stress is deleterious to your health.  

However, complex adaptive systems such as biological organisms are typically more nuanced, resistant to reductive explanations, and oftentimes counterintuitive from a “common sense” standpoint. The dose-dependent phenomenon of hormesis (discussed in the last post) is one such nuanced, complex, and counterintuitive response. If some is good, it doesn’t always follow that more is better, and conversely, if more is worse, it doesn’t always follow that some is bad. In the context of stress, whereas chronic stress leads to a maladaptive response and severe stress leads to an acute decline in health, moderate and intermittent stress yields an adaptive stress cellular response (ASCR). Generally, low to moderate stressors activate different signaling pathways, sensor molecules, transcription factors that mediate an adaptive stress response in cells and organisms. Duration and magnitude (dose-dependent) are the key variables that trigger this counterintuitive response. Two hormetic stressors I would like to discuss in this essay are fruits and vegetables and exercise.

Phytochemicals are biologically active compounds found in plants. A subclass of these chemicals serves as defensive agents against insects and microorganisms. In effect, they are natural biopesticides that prevent pests from eating plants’ buds, leaves, fruits, and roots. Although these phytochemicals are toxic to insects and microorganisms, they are produced in insufficient amounts to achieve toxic concentrations in the human body. Furthermore, equally as important, the direct antioxidant functions of these phytochemicals are negligible, as they do not accumulate in sufficient concentrations. Nevertheless, the consumption of these phytochemicals in the diet can stimulate a variety of hormetic adaptive stress responses that serve to protect organisms from future stressors. Examples of these phytochemicals and the plants in which they are concentrated, respectively, include the “superfood” hit list: sulforaphane (broccoli), allicin (onions and garlic), curcumin (curry spice), capsaicin (red pepper) and resveratrol (red grapes and wine). Sulforaphane and curcumin activate the transcription factor Nrf-2 which in turn activates antioxidant genes, allicin and capsaicin activate downstream growth factors through calcium influenced signaling, and resveratrol activates sirtuin-1-FOXO pathway. In sum, the activation of these pathways can protect cells against stress and thereby help injury and disease.

Similarly, exercise induces dose-dependent physiological adaptations in virtually every organ system of the body. In exercise physiology, the overload principle states that gradual increases in physiological demand for energy yield adaptive mechanisms that increase metabolic efficiency. Moreover, moderate dose exercise increases metabolic and oxidative stress in the short term which elicits an adaptive cellular response that increases their resistance to more severe stressors and insures against degeneration and decline. Epidemiological studies have shown that moderate exercise with adequate periods of recovery decreases the lifetime risk of several prevalent chronic diseases such as Alzheimer’s, diabetes, and stroke.  

The Renaissance physician, Paracelsus, recognized biphasic dose responses when he stated, “all things are poison, and nothing is without poison, the dosage alone makes it so a thing is not a poison.” Nevertheless, Paracelsus would be surprised by the ubiquitousness of this biological phenomenon and its extension into non-pharmaceutical domains. With regard to exercise and fruit and vegetable consumption, the majority of Americans are in no danger of moving into the toxic phase of the response as less than 15% of Americans meet the minimum CDC requirement for fruit and vegetable consumption and less than 25% meet the minimum exercise requirement. However, if as individuals and as a society we can move into the hormetic range of these stressors, we might be able to tap into the innate robustness selected by natural selection over millions of years of evolution to delay and decrease the rate of physiological decline associated with aging and disease.