The Devil is in the details. Make no assumptions. These are good rules to follow in life and they are particularly good to follow if one delves into the action packed world of science. Why? Because “WE” have a profound ability to fool ourselves. Missing the obvious because it does not fit our expectations describes human endeavors as divergent as spouse selection and scientific data interpretation. Typically we see what we want to see but occasionally unexpected results pique interest and new avenues of investigation are born. In other circumstances we turn a blind eye to observations that get in the way of “further validating” a solid, trusted theory. When the situation is highly counterintuitive, we experience the greatest resistance and problems.

Take hormesis, for example. Never heard of it? Neither had I until recently, when I was researching new developments in intermittent fasting. Hormesis describes a favorable adaptation to low dose exposure to an irritant/toxin/toxicant. Hormesis is a tough subject to make sense of in many instances as low doses of a given hormetic agent create the OPPOSITE effect of high dose. Here is a graph from Wikipedia for the visual learners out there:



Hormesis (above) is characterized by a graphical sign change as one moves
from low to high dose in contrast to classic dose response curves. (below)



Just to muddy the waters, not all agents are hormetic! Many agents follow a fairly simple dose response curve in their action, with perhaps a threshold of activity and then diminishing activity at higher levels. For the math geeks out there this can be described by a third order polynomial and is the backbone of modern pharmacology and toxicology. Let's now look at two interesting examples of hormesis: energetic or radiation hormesis and opiate-induced hormesis.

One might think radiation is a good thing if we can take a complete squid like Tobey McGuire “expose” him to an irradiated spider and find him later smooching on Kirsten Dunst… upside down…. in the rain…. Kreiki! Sign me up for the Hot Spider! Well, sequels are never as good as the original and it’s likely not a surprise that radiation is not good for you… unless you are going to be exposed to a whopping dose of radiation. As far back as the 1950s, it was observed that a small exposure to gamma radiation could greatly enhance survivability of a later large dose. Incidence of DNA damage, cancer and oxidative damage were seen to decrease greatly in test animals. This was about the time major progress was made in the development of vaccines and thus an analogy between “vaccination” and radiation hormesis has been made and is perhaps not too far off. Consequently this flavor of hormesis has been thoroughly studied and is largely accepted.

The situation of Opiate hormesis is a bit different and has left everyone studying hormesis scratching their collective noggins. I’m sure you are aware that opiates produce a sedative and analgesic effect which follows a fairly typical dose response curve with the following exception: At very low doses opiates produce increased pain perception. No one knows why and mechanisms are not forthcoming. Some contend that a gene/opiate interaction occurs which up-regulates some aspect of pain perception/transmission, but again, no one really knows what is happening.

You may be asking what does ANY of this have to do with Performance, Health and Longevity ? Possibly everything. We have looked at the idea that pulsatile, random stressors such as ketosis, intermittent fasting and exercise may be integral to disease prevention, health and longevity. Folks like Art DeVany have talked about it and appear to “live it” to great success. My intention with this article is to place some of the mechanisms of intermittent fasting, exercise and CRAN in more prominent and accessible context. To do that effectively we need to delve into a little chemistry and physiology. All of this will certainly increase your Geek Factor, but I promise this will also increase your AKP.

A ROS by any other Name…

Fifty years ago a cornerstone of modern medicine was put forth: The Free radical theory of aging . At the dawn of the nuclear age it was postulated that the production of Reactive Oxygen Species (ROS) from ionizing radiation, hydrocarbon combustion (smoking, automobile exhaust) and bad Elvis devotionals could damage cellular proteins and, perhaps more importantly, DNA, and lead to death and disease. Now the data on this was fairly conclusive in that if one exposed an organism to a given dose of gamma radiation, one could predict a given amount of DNA damage and associated ROS production. This early work inspired the notion that if ROS were “bad,” squelching the activity of ROS should be “good”.

An understanding of ROS prompted research into the therapeutic use of antioxidants as a means of slowing aging, preventing disease, and forestalling death. The hypothesis went something like this: Reactive oxygen species damage DNA and cellular proteins; this leads to disease and death. Therefore, any activity that decreases ROS production (antioxidant intake) should decrease ROS and consequently disease and death! Unfortunately, antioxidant supplementation never lived up to its expectations, and has actually proven to be deleterious to health and longevity in some cases . This is not to say, however, that antioxidants are worthless. Although supplementaiton with Vit E and other antioxidants has not proven to be a cure-all, it is interesting to note that high antioxidant intake from food has shown benefits in both epidemiological and clinical studies.

This has perplexed researchers, as this does not follow linear reductionism. Why would antioxidants from food be beneficial whereas isolated antioxidants in the form of a supplement are not only unhelpful but also potentially harmful? Like I said in the opening, the Devil is in the Details. It appears that cataloging a given chemical as simply an “antioxidant” may be too narrow a term. In many instances location within the cell as well as types and concentrations of other chemicals will determine whether a given agent is an anti- or pro-oxidant. This is true not only of cellular material in our bodies but also the mix of chemicals we ingest via plant materials. These chemicals have complex roles both in the plant and our mammalian physiology, and these roles are often subject to change as cellular conditions change. In essence, something that was an antioxidant in one circumstance may become a pro-oxidant in another. Interestingly, this appears to be a good thing with regards to health as viewed through the perspective of hormesis.

As you will see, the topic of antioxidants and free radical/ROS damage has proven to be as if not more convoluted than the investigation of dietary fat in health and disease.

OK, we need just a little more background before we talk about the underpinnings of Hormesis. Put on your goggles and lab coat Poindexter! Time for a wee bit of chemistry and physiology.

Weird Science

When we talk chemistry, we are in fact talking about electrons and how they exchange between elements and molecules. If you are not familiar with what constitutes an element, atom or electron, OR if you just want to geek-out on this stuff, you can check out a nice short description of these terms here. Most chemical bonding involves electrons setting up in pairs; however, free radicals have an unpaired electron that makes these little buggars VERY reactive and potentially destructive. This page from the Linus Pauling Institute is a little dated but it provides a good overview of antioxidants and free radicals, and it helps make a point that some large assumptions have been made regarding radicals and antioxidants. These assumptions require some revamping if we are to understand processes such as intermittent fasting and caloric restriction. Finally, you can find a good, simple explanation of the various types of radicals here. Now, do you need a thorough knowledge of radical chemistry to be a stud athlete or good coach? No, absolutely not. However, a steeping in these terms and an understanding of the free radical theory of aging will help put some new material into valuable context.

Hang with me for one more geek-fest as we look at glycolysis, and then, my friends, we can look at how hormesis may be the underpinning of intermittent fasting, exercise, CRAN, resveratrol and more.

The key point to get from the topic of glycolysis is that glucose is a substrate used in energy production. Through a series of enzymatically-mediated steps, glucose is cleaved into two molecules, each of which contains 3 carbons. These molecules are glyceraldehyde-3-phosphate (GA3P) and dihydroxyacetone-phosphate (DHAP). It is important to note that glucose, DHAP and GA3P are all potential glycating agents that can and do stick to cellular proteins creating what is known as advanced glycation end products (AGEs). Glycation can reduce the effectiveness of proteins or make them completely non-functional. Just a quick sideline. John Kyrk is the chap who created the animated glycolysis I linked to and he has a load of other cool animations on a range of biology topics. Check them out!

OK, you now have an understanding of what hormesis is and you suffered through a 101 course in chemistry and physiology and now grasp the finer points not only of the free radical theory of aging but also the reactive species produced in glycolysis. Let's look at CRAN, intermittent fasting, exercise and some phytonutrients—all agents known to improve health and longevity—and see if there is a common thread amongst all of them explained by hormesis.

Have A CRAN and a Smile

In earlier discussions we have looked at the similarities and differences of CRAN and IF. What has been postulated is that CRAN and IF work via similar but separate mechanisms1. In the case of CRAN we see a significant decrease in body weight, a slight increase in circulating ketone concentrations and some increases in cellular stress response mechanisms such as increases in heat shock proteins (HSP). In contrast intermittent fasting shows little or no decrease in body weight, significant increases in circulating ketone concentrations and significant increases in HSP expression. Our newfangled understanding of hormesis may offer some help in understanding what is happening in these two scenarios and why we might choose one over the other and how to optimize desirable results such as improved performance and a decreased rate of aging.

In the case of CRAN, we initially see an increase in circulating ketone concentrations and cellular stress mechanisms such as HSP expression; however, once the animal has reached a maintenance bodyweight (~40% of ad libitum weight), ketone concentrations and expressions of HSPs and other cellular chaperones are elevated compared to ad libitum animals but decreased compared to IF3. What may be occurring is an attenuation of glycolytic damage in both IF and CRAN and a potent hormetic effect in the case of IF3, 4.

If you recall from our previous geek-fest, glycolysis starts with glucose and ends in the production of GA3P and DHAP. All three of these agents, as well as the intermediates of glycolysis are potential glycating agents that can and do cause significant damage to cellular proteins. In the case of CRAN, glycolytic flux is reduced in total by overt caloric restriction. In simple terms, CRAN offers some benefits simply because less fuel is passing through metabolic pathways. It is intriguing that IF offers potential benefits in two ways. The first is transient and dramatic decreases in glycolysis during fasting. After a few hours the liver is typically emptied of its glycogen reserve and we see an up-regulation of gluconeogenesis from protein and a significant shift towards fat metabolism. How much of a shift towards either gluconeogenesis or fat metabolism appears to be a function of insulin sensitivity and up-regulation of fatty acid oxidation enzymes. It is important to note that at this point two separate but related elements of hormesis are at work: a reduction in glycolytic flux and an increase in fatty acid metabolism. The shift in fat metabolism actually produces a transient increase in oxidative stress in the mitochondria, which is likely responsible for the increased expression of chaperones, heat shock proteins and endogenous antioxidants. It is important to note, however, that excessive levels of antioxidants during this time will squelch this oxidative stress and stymie subsequent favorable adaptations5. It is also important to note that with re-feeding we witness a dramatic increase in glycolytic activity; however, in the adapted organism, this increase is quite short in duration and metabolism shifts to a fatty acid dominant, pro-ketogenic state5. OK that was a mouthful! Let's look at a diagram that covers the same information:


IF→ initial decrease in glycolysis→increase in fatty acid oxidation/ketone production→increase in transient oxidative damage→increase in HSP/chaperone and antioxidant expression + transient increase in glycolysis after re-feeding.

Now here is something that is REALLY interesting… many of the characteristics of aging and disease include excessive oxidative damage and mitochondrial pathology6. It appears that the chronic oxidative stress of overfeeding either overwhelms an organism’s adaptive capacity or never triggers the normal adaptive mechanisms that lead to health and longevity. This is the real importance of hormesis as a model for understanding IF, CRAN, exercise and phytonutrients that exert an anti-aging action. Ironically, we may need a pulsatile increase in oxidative stress to protect us from chronic oxidative damage, and, not surprisingly, chronic glycolysis may not be a great thing for aging effectively. Someone should let Dr. McDougal know his starch-based, 8-meals-per-day diet is perfect for accelerated aging!

We now have a much better understanding of the mechanisms that drive the results we observe with IF and CRAN. I want to look at one more concept that should help to put this whole process into perspective: Darwinian evolution on a cellular level.

That Which Does Not Kill You

All eukaryotic organisms have within their cells two information processing/storage centers composed of DNA. One is the nucleus of the cell and the other is mitochondrial DNA. The mitochondrion are thought to have once been free living organisms that became incorporated into larger, more complex cells and a symbiosis was established with the result being nearly everything on the planet that is not bacteria. A little reading on the endo-symbiotic theory of biology is sure to alienate you from friends and family, but leave you with a feeling of extreme hoiti-toiti-ness. So… metaphysical and political considerations aside, the accepted role of DNA, whether cellular or mitochondrial, is to replicate itself. You can get elbow-deep in information and game theory trying to describe the information processing elements of DNA and how this ties into Darwinian evolution… but that’s a topic for another publication. Part of the replication scheme appears to be adapting to the environment to optimize survivability and continued propagation. How this works has shifted from a picture of purely random events leading to “lucky” adaptations that favor survival to the almost Lamarckian view of epigenics. Perhaps not surprisingly, both random chance and an awareness of the environment appear to drive both micro and macroevolution.

In the case of hormesis we see both DNA centers (nuclear and mitochondrial DNA) affected by environmental factors the lead to a selection pressure favoring healthy phenotypes. If you recall our interview with Dr. Seyfried and the discussion of metabolic control analysis, you are familiar with the concept that subjecting cancer cells to either a ketogenic and or IF/CRAN environment selects for healthy cells, effectively culling unhealthy cancer cells7. This is due to the fact that cancer cells lack the cellular machinery to use fatty acids as fuel sources and rely solely upon glucose metabolism (glycolysis). Another facet of hormesis appears to be a selection pressure on the mitochondrion themselves as the acute stress of IF creates an overwhelming oxidative stress that healthy mitochondria can withstand and unhealthy lines cannot. The effective result is a cell population that is comparatively healthy and adaptive. We also need to consider two other factors. IF and CRAN increase the activity of DNA repair enzymes, helping to keep cells healthy and normal. This slows the speed at which an organism moves through its pool of stem cells which are utilized to replace damaged/dysfunctional cells. It appears that chronically high growth factors, as is associated with chronic overfeeding, burns through the stem cell pool8,9. Here is the money shot folks:

The hormetic action selects for healthy cell lines, whether we are talking just the mitochondria or the entire cell. This occurs via transient stressors that increase cellular stress mechanisms, typically by production of ROS, in an adaptive manner that mitigates deleterious levels of oxidative damage. Concurrently we observe the mitigation of chronic stressors such as glycolysis, which if left unchecked, overwhelm cellular repair mechanisms.

Sorry it took me so long to spit that out! So what is the take-home message here? How does an understanding of hormesis improve Performance, Health and Longevity? For starters, it puts antioxidant supplementation into a very different perspective. I would be conservative and keep dosages at or near physiologic levels. Also I think this lends support to a nutritional plan that minimizes glycolytic flux by shifting metabolism towards a fat adaptive state. For the athlete who requires ample muscle glycogen to perform, I think this supports an argument for squirreling glycogen into the muscles during the post workout window. I’m still not sure if hammering a glucose polymer drink is a good idea, and prefer whole food consumed in a real meal format, but extreme situations may call for extreme measures. It would appear the post workout window would be preferable to spreading carbs throughout the day, and for certain it makes an argument to minimize carbs before bedtime to get some mileage from that period of “forced” fasting. This also squares nicely with previous discussions of seasonal eating and utilizing a period of purely ketogenic eating, perhaps with some intermittent fasting, to select for stress resistant, healthy cell lines (that means you).

Researching and writing this article has not moved me to change much of what I was already doing. I do, however, better understand what is happening on a cellular level when I choose a lower carb paleo approach to eating, with occasional intermittent fasting. I think this information is fascinating and real understanding is only beginning. Perhaps more than anything else, this paper has encouraged me to make no assumptions while keeping an eye on the details.