What does not kill you makes you stronger

Even poisons and toxins can sometimes be good for you, if consumed properly and in tiny amounts. No, I’m not talking about homeopathy. There are much more pleasant ways to ingest potentially dangerous substances, and most of us do it on a regular basis – fancy a glass of wine after a tough workday? Some studies have reported beneficial effects of light-to-moderate alcohol consumption, and alcohol consumption has also been associated with reduced sudden cardiac death risk (Albert CM, Circulation 1999; Chiuve SE, Heart Rhythm 2010; Bertoia ML, Am J Clin Nutr 2013), although this association is still quite debatable. But what is the reason behind this? When discussing health-related effects of alcohol, red wine usually comes to mind as a “healthy” alcohol source (remember the Mediterranean diet and “the French paradox”?). Interestingly, the above mentioned studies meant alcohol per se, any reasonable sourse of EtOH, not red wine only. What could be behind the seeming benefits of alcohol consumption?..

Another common “toxin” that we ingest on a daily basis is fructose. If it’s coming from natural sources, coupled with lots of fiber (read: fruit or berries), it’s actually not that bad for you, but the way it’s metabolized in the liver (which is very much similar to the way alcohol is metabolized), suggests it is regarded as a toxin by the body. Also, if you think about how bad it is for us when consumed in pure, isolated form (read: high-fructose corn syrup), it actually does make sense. So why is eating fruit commonly viewed as a vital part of an overall healthy diet?

Let me guess your answer: antioxidants.

Fruits and vegetables are healthy because they contain a lot of antioxidants.

What can I say to that? Yes, as a matter of fact, they do. But that’s not what makes them healthy.

First of all, antioxidants consumed from food or supplements are far less powerful than the ones produced by our own body when oxidative stress response mechanisms are activated. Also, certain levels of oxidants are not only healthy – they are crucial to certain functions on the intracellular level. Of course, when we talk about oxidative stress in a pathological condition (e.g., atherosclerosis), the levels of oxidants produced are far exceeding the beneficial levels. But I digress! So what is it in the fruit that makes it good for you? Hint: the underlying mechanism also contributes to the benefits of intermittent fasting, caloric restriction, exercise and intellectual challenges.

By now you might have guessed that I’m talking about some kind of “good stress” type of thing here. The “good stress” – “pre-conditioning”, if you will – I’m referring to is hormesis. “Hormesis is what makes fruit and vegetables healthy, not antioxidants”, to cite Mark Mattson (Mattson & Calabrese, New Scientist 2008). So what is hormesis? The term originally comes from the field of toxicology and refers to the ability of some drugs to induce a biphasic response by having a toxic effect at high doses but a beneficial one at low doses (see Fig.1). Alcohol, for example, is discussed as a potential inducer of hormesis, although it has never been proven. Many trace minerals in our diet work in a hormetic sort of way: for instance, selenium is absolutely essential to our well-being, albeit at very small doses; however, it can be very much toxic at moderate and high doses. The same is true for oxygen: we literally can’t breathe without it, but give us too much and it becomes toxic to us. Same thing happens when we eat fruits and vegetables, which contain certain phytochemicals that induce hormesis, such as: sulforaphane (broccoli), resveratrol (grape skins), curcumin (turmeric), caffeine (coffee), ECGC and other catechins (abundant in green tea, but also present in black tea). All these plant substances are potentially toxic for us, and yet they have proven to be quite beneficial when consumed at low doses. Moreover, the response they initiate in our cells is probably the main reason behind the health benefits of fruits and vegetables, not so much because they contain antioxidants.

Figure 1. Hormesis. Adapted from Gems & Partridge, Cell Metabolism 2008.

Hormetic response induced by fruits and vegetables is a result of an adaptation that has occurred at some point during the course of evolution: our organisms have evolved in a way that we can consume stuff containing potentially dangerous substances (like biopesticides) and get away with it! Why the heck did we start eating plants in the first place, anyway? Energy and nutrients, that’s why! (Also, plants cannot run away from us like animals – that’s why they counterevolved to produce all those dangerous things in the first place.) So to manage toxic chemicals those plants contain, we evolved to obtain certain detoxification mechanisms to metabolize and excrete these “poisons”, but also to use those substances to our advantage by activating certain pathways in the cells that are beneficial to us in the long run. Isn’t that grand? Smart little buddies, our cells.

Some phytochemicals (in particular, phenolic compounds) can directly act as antioxidants, but their concentration in the plants is so low, that we, humans, would have to eat enormous, unrealistic amounts of fruits and vegetables to reach an appropriate concentration of plant antioxidants on a cellular level. Instead, what happens is that phytochemicals – those potentially harmful at high doses biopesticides produced by plants – activate intrinsic antioxidative defense systems, like the Nrf2 pathway. Activation of stress-response pathways in the cell results in a protective effect that can counteract detrimental effects of aging or disease on the organism. So, basically, phytochemicals are slightly poisonous to the cells, making the cells more robust to more detrimental stressors. But if you overdo it with phytochemicals, it might result in cell death. What does not kill you makes you stronger, indeed. Fortunately, noxious effects mostly occur before a highly toxic and dangerous amount of phytochemicals is consumed.

Consumption of phytochemicals (through fruits and vegetables or via supplements) can increase resistance to many types of stressors on the molecular, but also on the organismal level. It can lead to stimulation of internal antioxidative activity, protect against harmful effects of inflammation, support energy metabolism and activate clearance of damaged macromolecules. All those protective effects are especially important to the aging population, since phytochemical-induced responses can potentially counteract age-related changes. Indeed, animal studies confirmed a positive effect of citrus fruit and berry extracts (which contain an active compound quercetin) on lifespan and demonstrated their various anti-aging properties. Curcumin, resveratrol and EGCG (the main active polyphenol in green tea) act on the insulin receptor pathway – a major intracellular pathway that regulates aging, growth and, of course, insulin sensitivity. Resveratrol and EGCG are also known to activate sirtuins, particularly SIRT1, that targets multiple proteins involved in numerous stress response pathways, activation or blocking of which can lead to decreased inflammation, Alzheimer’s disease (AD) and cancer risk. Not bad, huh? So why don’t we just treat AD patients with those fruits and veggies?

Unfortunately, when it comes to disease prevention and disease management, plant phytochemicals seem to be more useful for the prior. Once the disease is at an advanced stage, not much can be done. Small beneficial effects produced by the ingestion of plant phytochemicals might be of no use anymore when a person is already very sick, and more harsh interventions are needed. Nevertheless, some phytochemicals (e.g., cannabinoids) are being used in clinical studies and to manage certain conditions. Drugs based on natural phytochemicals are being developed and widely investigated. Word of advice, though: why wait for the drug, when you can treat yourself to/with fruits and veggies to promote health and enjoy their delicious taste? Pair them with a good cup of coffee – caffeine decreases depression risk – or green tea, and you are good to go!

For a more detailed overview of various phytochemicals that can induce hormesis and mechanisms of their action, I’m referring you to an excellent and very extensive review by Lee and Mattson in Pharmacological Reviews, June 2014, entitled “Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System”.

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Other hormesis-inducing agents that are crucial to health maintenance include intermittent challenges, such as high-intensity interval training or fasting for short periods of time. How does challenging yourself intermittently improve health and what are the benefits of intermittent fasting vs. simple caloric restriction? Stay tuned!