Hormesis: Nature Steel Thyself

Ever wondered exactly why is exercise good for you? What does it do? How about green tea or garlic? Just why are they good for our health? Well, the answer may just turn out to be something called hormesis. Never heard of it? Don’t worry, you are not alone, but if the work being carried out by pioneers like Prof Ed Calabrese and his team bears out then everything from textbooks, to the practice of medicine, toxicology and the way we think about health may have to be rewritten. So, what exactly is hormesis?

Defining hormesis

If you do a quick search of the internet you may well find a number of health blogs, ancestral/paleo diet sites, not to mention more than a few homeopathy sites that talk about hormesis. For the record, homeopathy and hormesis should not be confused, hormesis is a basic biological principle whereas homeopathy is a pseudoscience that has no supporting evidence. Often these sites will explain hormesis in terms of a positive or beneficial effect gained from an agent (be it chemical or physical) at low doses where the same agent would produce a toxic or negative outcome at higher doses. For simplicity’s sake that’s all well and good, but the situation is a little more complex and a slightly different definition would serve to understand the issue better.

In a paper titled Defining Hormesis, Dr Calabrese, who, with his team has probably done more research into the subject than anyone, talks about ‘decoupling beneficial effects from the definition of hormesis’. He argues, quite rightly, that the simple idea of a beneficial effect is difficult to determine because of the sheer complexity of biological systems. Now that’s not to say there aren’t benefits, there are, which I’ve detailed below, but as Calabrese argues, it depends on the system and how you define ‘benefit’. For example, it has been shown that low doses of antiviral, antibacterial and anti-tumour agents can enhance the growth of their respective targets whilst high doses inhibit growth. In these scenarios low doses would be detrimental to the human host. Low doses might also enhance longevity but at the expense of fecundity, or vice versa, Calabrese also argues. So, perhaps it might be better to talk in terms of hormesis being a low dose stimulation, high dose inhibition phenomenon leaving aside the idea of ‘benefits’ and looking at the issue on a case by case basis.

Other factors need to be considered, too, chief among them; time. Figure 2 shows an example dose-time-response hormetic curve. At the first exposure we see a somewhat linear decrease in function as dose increases. At the second exposure, however, we see a modest increase in response above the control. At the third exposure we see a still greater response against control.

What’s happening here is that at the first exposure the cell/system is essentially caught unawares and whilst routine regulatory processes will be in effect to maintain homeostasis the cell/system isn’t geared up to deal with the additional stress of the disruptive agent. However, biological systems are adaptive, they need to be in an ever-changing environment. Cells and biological systems have myriad ways of regulating and maintaining homeostasis. Providing that the initial stress wasn’t overwhelming i.e. not fatal, the cell will begin to enact a repair process in order to restore homeostasis. What tends to happen though is that there is a slight overcompensation, most likely, a result of evolutionary selection. In evolutionary terms overcompensation would not only allow for repair of damage caused by the first exposure, but provide a buffer against further subsequent exposures to the same agent/stressor.

In studies, both conducted and collated by Calabrese, we see that in 80% of hormetic responses there is a ceiling and that overcompensation rises no farther than 30-60% above control. This again is most likely due to evolution honing the process. In order to repair damage and bring about homeostasis, the system will manufacture a number of molecules and proteins, either for repair or stabilisation. This is an energy intensive process, and nature tends to be thrifty with its resources and so it would appear that an overcompensation of between 30-60% above control has evolved so as to provide adequate response whilst making the most efficient use of resources.

This same thriftiness also means that the hormetic effect is time bounded. The manufacture of additional proteins and activation of additional pathways is simply too costly in terms of the limited resources available and so over time these additional mechanisms will be recycled and down regulated.

The process described above is termed overcompensation hormesis, though there also exists evidence for a slightly different process: direct stimulation hormesis. With direct stimulation hormesis, as the name suggests, response rises directly in relation to the stressor following a similar curve to the one shown in graphic below

Basic hormetic response curve. The upper graph shows a plots a typical response as dose is increased. The lower shows a typical overcompensation response at three different exposures.
Basic hormetic response curve. The upper graph shows a plots a typical response as dose is increased. The lower shows a typical overcompensation response at three different exposures.

Homeostasis
Homeostasis is the ability to maintain a constant internal environment in response to environmental changes. All living organisms need to maintain a constant internal environment in order to continue living. Without balancing things like pH, temperature, minerals, sugars and a whole host of other factors the chemical reactions necessary for life would become unsustainable and the organism would die. Homeostasis describes the set of processes by which the organism maintains its constant internal environment against the ever changing external environment.

Exercise

The act of exercising places our bodies under stress in several ways. If you were to take blood samples both directly before and after a period of intense exercise you would see a huge upwards shift in the levels of inflammatory factors, cortisol, oxidative stress etc. The physical stress on the body would also result in micro tears in muscle tissue. On the face of it this might seem like a bad thing, but these all of these things stimulate an hormetic response that leads to many benefits attributed to exercise, from larger, stronger muscles to increased cardiovascular fitness and increased ability to deal with oxidative stress.

Alcohol

It’s widely known that excessive consumption of alcohol can be detrimental to health and is associated with numerous diseases including heart disease, liver cirrhosis, cancer and some neurological disorders. However, moderate consumption of alcohol leads to an overall reduction in mortality particularly when it comes to heart disease and stroke.

Smoking

As difficult as it may seem to believe there is substantial evidence to suggest that cigarette smoking may protect against Parkinson disease. Articles published in the journal Neurology note a lower risk of Parkinson disease among current and former smokers. Whilst they fail to specify a mechanism the 2007 paper entitled Temporal relationship between cigarette smoking and risk of Parkinson disease concluded

“The lower risk of Parkinson disease among current and former smokers varied with smoking duration, intensity, and recentness. The dependence of this association on the timing of smoking during life is consistent with a biologic effect.”

This may point to a time bounded hormetic mechanism induced by smoking that infers protection against Parkinsons. Does this mean you you should take up smoking? No. But, I think, it highlights the complexity of hormesis whilst one substance may provide a benefit in some sense it can also wreak havoc on other systems and processes.

Sunlight

One of the most visible examples of hormesis at work is the suntan. A darkening of the skin in response to direct sunlight is the body’s way of trying to limit damage. We also know that frequent sun exposure is good for us in terms of vitamin D production and blood pressure through the liberation of nitric oxide, but excessive exposure can lead to sunburn and increased risk of skin cancer.

Calorie Restriction/Intermittent Fasting

Calorie restriction diets place the body under mild stress. Studies have shown that long periods of this mild form of stress often boosts the health and lifespan of many species. In recent years research has turned towards intermittent fasting (IF) which reproduces many of the benefits of calorie restriction whilst being much easier to adhere to. IF upregulates brain derived neurotrophic factor (BDNF), a neuroprotective neurotransmitter. Low or depressed levels of BDNF have been associated with poor memory and learning problems, psychiatric disorders and diseases like Alzheimers.

IF also boosts autophagy, a process by which cells digest and recycle any non-essential or damaged proteins. This essentially acts as a cleaning process removing unwanted clutter that may over time lead to damage and eventual cell death.

Exposure to temperature extremes

Exposing both animals and people to extreme temperatures has been shown to produce beneficial effects so much so that it’s now routinely used in a clinical setting. Exposing people to temperatures of 80-90ºC for around 20 minutes have been shown to improve a number of chronic conditions.

At the other extreme, exposing people to temperatures of between -110ºC to -140ºC for 2 minutes has been claimed to improve a range of conditions from chronic inflammatory diseases, dementia, Parkinson disease and depression. Whilst exposing yourself to such low temperatures is not only extreme but requires high technology and close medical supervision there is evidence to suggest that benefits can be reaped by more readily attainable cold temperatures that that by simply taking a plunge in cold water or standing under a cold shower for a few minutes can also produce benefits.

Plant phytochemicals

Whilst it’s commonly known that plant phytochemicals are good for our health few seem to realise that many of these chemicals evolved as a defence mechanism and act as natural pesticides. Consumed in large enough amounts these ‘poisons’ would also prove detrimental to us, but in the quantities we receive in the normal course of eating the plants the provide a low level of cellular stress which induces a hormetic response.

Further Reading

Mao, L.; Franke, J. Hormesis in Aging and Neurodegeneration—A Prodigy Awaiting Dissection. Int. J. Mol. Sci. 201314, 13109-13128

Son, Tae Gen, Simonetta Camandola, and Mark P. Mattson. “Hormetic Dietary Phytochemicals.” NeuroMolecular Medicine 10.4 (2008): 236-46. Print.

Hormesis As A Pro-Healthy Aging Intervention In Human Beings?Francine Z.Marques – M. AndreaMarkus – Brian J.Morris – Dose-Response – 2009

 

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