Miller JZIf you have any physiology, performance, or nutrition related questions, email Ben at


 Paracelsus, the father of toxicology, stated, “all things are poison, and nothing is without poison; only the dose permits something not to be poisonous.” The word used to describe this phenomenon is hormesis.  What hormesis means, simply, is that with increasing doses there are increasing benefits until a point where increasing the dose further has detrimental outcomes (see figure).  The concept of hormesis has its roots in toxicology, but its application reaches far beyond toxicology to almost all biological stimuli.  For example, sun exposure, oxygen, and even exercise are beneficial to a certain point, but too much can lead to skin cancer, toxicity, or the breakdown of tissues, respectively.  In the last column I mentioned that more is not always better.  This column will strive to illustrate why that is the case.  


The human body has a remarkable ability to adapt to the stresses imposed on it.  Adaptation to stress can happen at the cellular level or can require the coordination of several of the body’s systems.  Adaptation to stress is most easily explained at the cellular level.  In order for anything to be a stress, it has to be sensed.  Cells have a vast array of sensors that detect the changing environment around them.  When a change in the environment is sensed a series of signaling events happen in the cell so that the cell can adjust to the new environment.  For example, when you lift weights, the muscle cell senses a mechanical stress.  That mechanical stress puts into motion a series of events inside the cell, which results in the DNA of that cell making the blueprint to make more contractile proteins.  The making of more contractile proteins is what makes the muscle bigger.  Therefore, lifting the weight caused the making of more proteins that make the muscle cell stronger so that the next time the weight is lifted, it is not as hard to lift – the muscle adapted to the stress.  I know I have mentioned versions of this scenario before, but the reason that it is so important to understand this concept for the current column is that I need to make the point that interfering with the signaling can disrupt the ability of the cell to make necessary adaptations (taking away the signal leaves nothing to adapt to).  



Returning to hormesis, the above paragraph explains how the body performs stress-response.  Again, a small stress triggers events that make the cell stronger, while too large of a stress will often lead to maladaptive responses.  An excellent example of hormesis is reactive oxygen species (ROS), which some of you know as free radicals.  If you canvassed 100 people, I would be willing to bet that 95 of them will say that ROS are bad for you.  Indeed, too many ROS can lead to cellular damage and some think that ROS damage is one of the primary causes of aging.  However, ROS are only bad if they are in excess (hormesis).  Small amounts of ROS are actually very powerful signals in the body.  When performing aerobic exercise (like biking) your mitochondria (powerhouse of the cell) use oxygen to create ATP (the energetic currency of the body) from food-derived molecules.  When using that oxygen, the mitochondrial occasionally slips up and makes ROS – it is just something that happens and it happens quite often.   The making of ROS, however, is a very good signal for the cell to make more mitochondria.  Making more mitochondria is one of the primary reasons we train since a high amount of mitochondria is requisite for high rates of energy production.  Recall the weight lifting example of making a bigger muscle, the endurance exercise equivalent to that is making new mitochondria in response to, among other signals, ROS.  


To summarize so far, hormesis means something in small amounts is good while too much of it is bad.  The way this works is that a signal triggers a cellular adaptation to make you better at dealing with a stress.  However, this only works to a certain point where a response then becomes maladaptive.  ROS are an excellent example of hormesis.  With this background, I can now give an example from the nutrition world of why more of some things are not good.  


There is a multi-billion dollar industry centered on vitamins and supplements.  In addition, how many times have you seen or heard advertising for product that touts the product’s anti-oxidant properties?  The advertising of anti-oxidants is predicated on the thought that ROS are bad and must be dealt with.  Further, anti-oxidants are often targeted at endurance athletes because higher use of oxygen can result in more ROS production.  However, I mentioned above that ROS are also very powerful signals to cause adaptation to aerobic exercise.  A group of researchers decided to take a look at whether vitamin C and E, two vitamins used for their anti-oxidant properties, might interfere with the ROS signaling during exercise and sure enough it did – in a very detrimental way.  There is now a body of literature that shows that taking vitamin C and E in normal recommended doses can blunt the mitochondrial adaptations to aerobic exercise.  In one study rats were put on an treadmill exercise program for 6 weeks with one group receiving no treatment and the other group being supplemented with vitamin C.  As expected the exercise training improved time to fatigue by 187%.  However, the rats taking vitamin C only improved by 26%!  There have now been studies performed in both rodents and humans further elucidating the mechanisms of the blunting of these positive outcomes by anti-oxidants. Work in our own lab studying the making of mitochondrial has found the same detrimental outcomes when using vitamin C.  Last, meta-analyses (a statistical analysis done on the outcomes from a many studies combined) have concluded that the taking of anti-oxidants such as Vitamin C, A, and E have no beneficial (and sometimes detrimental) effect on some disease processes.  Therefore, the majority of outcomes document detrimental outcomes from anti-oxidant supplementation.  


The vitamin C and E example is just one example of how more is not always better.  By no means does this mean that one should not eat an orange or other healthy fruits and vegetables that contain vitamins.  A well-rounded diet does not provide such large amounts of the vitamins that one swings to the detrimental side of the hormesis curve.  In addition, fruits and vegetables also contain phytochemicals, which have their beneficial effects on health by hormetic mechanisms, and other beneficial compounds.  Although the athlete psyche is usually that more is better, this is clearly not the case.  


Figure from: Son TG, Camandola S, Mattson MP.  Hormetic dietary phytochemicals. Neuromolecular Med. 2008;10(4):236-46.


Paper of interest:  Gomez-Cabrera, M.-C., Domenech, E., Romagnoli, M., Arduini, A., Borras, C., Pallardo, F. V., et al. (2008). Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. The American journal of clinical nutrition, 87(1), 142–149.