Inflammation can be one of the most misunderstood aspects of health when viewed with reductionist thinking. Part of the misunderstanding is based on the assumption that model organisms, such as baker's yeast (Saccharomyces cerevisiae), the fruit fly (Drosophila melanogaster), mice, rats and dogs can tell us what also happens in humans.

That is, caloric restriction without starvation has extended the lifespans of these organisms. This idea was based on the assumption that restricting the consumption of total calories would lower the total metabolic rate and the production of reactive oxygen and nitrogen species (RONS) as well as free radicals. This led to the free radical theory of aging, in which it was proposed that the accumulation of damage caused by free radicals causes aging and eventually death. That is, the oxidative metabolism of proteins, fats and carbohydrates in the mitochondria in cells produces RONS and free radicals, which can oxidize and damage DNA, lipids and proteins. This can lead to autoimmune diseases and cancer as well as cardiovascular and neurodegenerative diseases. So, people in almost all countries were encouraged to eat foods that have a high antioxidant capacity. Also, artificial in vitro (in glass, or test tubes) tests for total antioxidant capacity emerged. They were based on measuring the destruction of oxidized test compounds by direct reactions with the antioxidants in foods.

Many dietary supplements arrived on the market. They contained purified antioxidants, such as resveratrol and EGCG that were and still are widely assumed by many to be quite healthy at any dose. Even today, many advertisements for popular ‘superfoods’, beverages and dietary supplements highlight the huge antioxidant activities of their products. This assumes that dietary antioxidants exert their health effects by reacting directly with RONS and free radicals, destroying them. They were very popular years ago and led to one ‘superfruit’, açaí, being identified as having the highest antioxidant activity of any food. So, for several years, the U.S. Department of Agriculture (USDA) listed the in vitro antioxidant capacities of many foods and spices.

However, as scientists and physicians learned more about human nutrition, they realized that the caloric restriction that worked for other organisms did not work for humans. This required changing the paradigm from reductionist thinking to systems thinking. Reductionist thinking assumed that there is a linear relationship between the dose and the physiological effect of potential toxins. It also assumes that if a small amount of an antioxidant that is present in food (like EGCG in green tea) is healthy, then much larger amounts in a dietary supplement would be even healthier – especially if they were ‘natural’. In contrast, systems thinking does recognize the nonlinear and cyclic nature of life, while accepting the concept of hormesis. That is, hormesis recognizes that moderate levels (or doses) of RONS are needed for good health.

In addition, the antioxidant paradox became apparent. Most dietary antioxidants have low bioavailabilities. They don’t reach the target organs at a high enough concentration to have a direct effect. Also, giving large doses of dietary antioxidant supplements to human subjects has seldom had any preventative or therapeutic effects. We learned that most antioxidants (especially phenolic compounds) don’t work by reacting directly with RONS and free radicals. So, the USDA removed the list of antioxidant capacities from their website years ago.

At the same time, it is important to use systems thinking and realize that some inflammation can be not just a cause or a symptom of many diseases, but it is also essential for good health. When pathogenic microorganisms invade the body, immune cells kill them by causing oxidative damage and inflammation. Although there may be some collateral damage to the surrounding healthy cells and tissues, this does get repaired.

So, let’s look closer at how antioxidants really work. Even though vitamins A and C as well as CoQ10 can react directly with RONS and destroy them, other antioxidants seldom do this. Moreover, many RONS act as biochemical messengers in normal, healthy metabolism. RONS have nonlinear, hormetic effects. At low concentrations, they can have definite health effects. Exercise is an example of hormesis. When we exercise, RONS are produced and there is some temporary inflammation. Vigorous exercise increases blood flow, oxygen consumption and the production of RONS, while modulating the growth factor signaling cascade and increasing the availability and function of neurotransmitters. That is, exercise induces oxidative stress. Regular exercise causes adaptive changes in cellular antioxidants. Redox balance regulates the generation of force in muscles. Maximum force is produced when the redox state is balanced. That is, there should be a proper balance between the concentrations and activities of pro-oxidants (RONS) and antioxidants. RONS are required to promote the healthy responses of muscles to exercise.

Still, antioxidants are needed. Many dietary antioxidants can activate our own endogenous antioxidant system. Foods and beverages that have high concentrations of antioxidants can help prevent cardiovascular disease (CVD) and many types of cancer. They exert their health effects by activating the endogenous antioxidant response elements (AREs) that are present in our cells. However, the antioxidant system must be turned on only when it is needed. So, the signaling system that controls AREs is carefully controlled by a protein called Nrf2. The Nrf2-ARE signaling system can prevent CVD by preventing smoldering inflammation. It does this by activating the natural antioxidant systems in cells. This helps prevent smoldering inflammation.

Smoldering inflammation is a chronic, relatively low level of inflammation that is caused by an excess of RONS and free radicals. However, like so many things in life, the Nrf2-ARE signaling system must be balanced. That is, even though it may be quite healthy to activate it to a limited extent by consuming dietary antioxidants at the concentrations that they occur in foods, it should not be over-activated. If the Nrf2-ARE system is over-activated, it can cause cardiac hypertrophy and remodeling. This could lead to CVD. Finally, multidrug resistant cancers often have an overactive Nrf2-ARE signaling system. So, even though the lower concentrations of dietary antioxidants that are present in many fruits and vegetables may help prevent CVD and cancer, the much higher concentrations and doses in dietary supplements may help cause CVD and multi-drug resistant cancer.

Moreover, it is worth noting that the prescription drug metformin (Glucophage®) can increase the lifespan of cancer patients by inhibiting their natural Nrf2/ARE system. In contrast, moderate doses of many dietary antioxidants in green tea as well as many colorful fruits and vegetables can activate this system. This can prevent the accumulation of too many free radicals and RONS before a person gets cancer or CVD. It’s also possible that the much higher doses of pure dietary antioxidants (like ECGC and resveratrol) in dietary supplements can also prevent the accumulation of RONS. This might be able to prevent many diseases caused by smoldering inflammation (like cancer and CVD). However, once a patient gets cancer and starts chemo- and/or radiation therapy, such dietary supplements could become deadly. That is, cancer cells can hijack the Nrf2/ARE system to make them multidrug resistant and resistant to chemotherapy. So, the same things that prevent cancer can reduce the lifespan of patients who get cancer and start chemo- and/or radiation therapy. So, physicians and oncologists who are treating patients with chemo- and/or radiation therapy should probably warn their patients about the potential dangers of taking dietary supplements that contain high doses of pure antioxidants. Moreover, the use of such supplements should be carefully controlled in the MILES and TAME clinical trials that will look at the effects of metformin on longevity.

References
1. Smith, Robert E. Systems Thinking in Medicine and New Drug Discovery, Volume One. Cambridge Scholars Publishing, Newcastle upon Tyne, 2018.
2. Smith, Robert E. Systems Thinking in Medicine and New Drug Discovery, Volume Two. Cambridge Scholars Publishing, Newcastle upon Tyne, 2018.
3. Ajit, Deepa et al. Phytochemicals and botanical extracts regulate NF-kB and Nrf2/ARE reporter activities in DI TNC1 astrocytes. Neurochemistry International 97: 49-56, 2016.