Polyphenols: Activators of Our Genes, Guardians of Our Gut

Polyphenols: Activators of Our Genes, Guardians of Our Gut
Once you have reduced diet-induced inflammation by the Zone Diet, and then sufficiently resolved residual cellular inflammation by producing adequate levels of resolvins using omega-3 fatty acids, the third and most complex stage of the Resolution Response is to repair the tissue damaged by increased exposure to cellular inflammation. Your primary dietary tool to achieve that goal is high-dose polyphenols.

The story of polyphenols is strongly intertwined with the activation of AMP kinase.  AMP kinase is the master genetic switch that controls your metabolism (including the repair of damaged tissue).  Thus, your ability to activate AMP kinase ultimately controls your healthspan. How activation of  AMP kinase accomplishes this goal is complex, so I put the mechanisms in Appendices E and F.

Just as the Zone Diet reduces the activation of the genetic master switch of inflammation (NF-kB) that causes inflammatory damage, polyphenols activate the genetic master switch of metabolism (AMP kinase) that heals that inflammatory damage.  This represents the final stage of the Resolution Response.

Background
Polyphenols are the complex chemicals that give plants their color.  The more colorful the plant, usually the higher the polyphenol content.  This is why vegetables and fruits are the plants that have the highest concentrations of polyphenols.   Although there are approximately 8,000 known polyphenols, and probably twice that number that have not been structurally analyzed, little was known about the biological activities of polyphenols before 1995.  This was because we didn’t have the technology to understand how they activate genes.  It is now clear that the levels of polyphenols in the diet are critical for the final stage of the Resolution Response to be activated.  The extent of the repair process depends on the remaining level of the inflammation caused by the initial injury may have been further amplified by continuing diet-induced inflammation.  Unfortunately, this often leads to fibrosis if the final step of the Resolution Response is not completed.

There is a great deal of epidemiological data that shows the increased dietary intake of foods rich in polyphenols (primarily vegetables and fruits) are associated with lower rates of chronic disease and mortality. We also know that increased levels of polyphenols in the urine (indicating their absorption into the blood) are also strongly associated with reduced mortality and frailty in elderly populations.

We now are beginning to understand how polyphenols work.  They activate the master genetic switch of your metabolism.  This is the gene transcription factor is AMP kinase and represents the key to a longer healthspan. The story of AMP kinase and its vast array of actions is complex so I put it Appendix F.  However, the repair process of the Resolution Response is governed by the ability to AMP kinase to maintain the quality control of your mitochondria that generate the energy needed for the repair of damaged tissue.

AMP Kinase and Polyphenols
Polyphenols are natural activators of AMP kinase, but through an indirect route.  They work by activating another gene transcription factor called SIRT that in turns activates AMP kinase as described in Appendix E.  This begins to explain why the consumption of high levels of vegetables and fruits are associated with greater health and longevity. That’s also why you have to eat a lot of vegetables and fruits (about 10 servings per day) to consume enough polyphenols to start observing the benefits of activating AMP kinase.  But there is another challenge with this dietary approach because the vast majority of polyphenols are not very water-soluble, so only relatively small amounts of polyphenols get into the blood. This is actually good news for your gut since their concentrated presence in the gut will activate AMP kinase in the cells that line the gut wall thus improving gut health and reducing a potential source of inflammation.  This means for increasing your healthspan that you will need a combination of both water-soluble polyphenols and water-insoluble polyphenols.

This importance of water-soluble polyphenols for human health is reinforced by studies in Italy studying elderly individuals following the traditional Mediterranean diet in remote regions of Tuscany. When the researchers initially looked at the amounts of polyphenols consumed by these individuals and their mortality, they found no relationship.  However, when the researchers looked at the levels of polyphenols in their urine (which is a marker of the polyphenols that actually entered the blood), they found those individuals with the highest levels of polyphenols in their urine had a 30 percent reduction in mortality.
Therefore, the optimal activation of AMP kinase in your body requires finding appropriate polyphenols that not only activate AMP kinase, but also are water-soluble so they can enter into the blood.  Now the number of potential polyphenol candidates for a longer healthspan drops dramatically.  The primary candidates belong to a subclass of polyphenols known as delphinidins found in berries, and in particular blueberries.  The secret is how to get as many delphinidins in your diet as possible.

Polyphenol Extracts
The levels of polyphenols found in vegetables (about 0.1 per cent by weight) and fruits (about 0.2 per cent by weight) are low. Of course, the levels found in refined carbohydrates like white bread and white pasta are zero. Thus, you need to eat a lot of fruits and vegetables every day to maintain the adequate intake of polyphenols for improving  gut health. Getting adequate levels of water-soluble polyphenols necessary to maximally activate AMP kinase in your body is an even greater challenge.

A potential solution is the processing of unique polyphenol sources to yield concentrated extracts. These extracts make it possible to consume adequate levels of polyphenols to generate consistent therapeutic benefits for your body’s cells as well as in your gut. The two best dietary sources are the blueberry family for water-soluble polyphenols and cocoa beans for water-insoluble polyphenols.

The extraction methodology for any polyphenol extract starts with making a slurry of the raw material source, followed by dehydration of the slurry generating a dry crude powder. This dehydration step usually doubles the polyphenol concentration. The dried powder can then be further extracted using alcohol to further increase the polyphenol content because polyphenols have a higher solubility in alcohol compared to other components in the dried crude polyphenol powder. This explains why drinking red wine has been the classical way to consume higher levels of polyphenols as opposed to eating massive amounts of grapes or other fruit (like blueberries).  Finally, the alcoholic extracts can be further purified using chromatography to generate refined polyphenol extracts approaching 40 percent polyphenols by dry weight.

Unlike fruits, cocoa beans contain very little water, but a lot of fat.  To produce cocoa powder, the cocoa nibs are first separated from the seeds, then milled to produce a slurry of cocoa powder and cocoa butter called a chocolate liquor.  Now you can separate the cocoa butter from the cocoa powder to get an isolated cocoa powder that is relatively rich in cocoa polyphenols.  That’s why raw cocoa powder is so bitter when you taste it.  The reason is that polyphenols interact with your bitter taste receptors in the tongue.  Just as you can extract dried polyphenols powders with alcohol, you can also extract the cocoa powder with other organic solvents to get an even higher percentage of polyphenols also approaching 30 percent by weight.

Blueberry and cocoa polyphenol extracts have provided most of our clinical data on the benefits of polyphenols.  Bottom line, blueberry polyphenol extracts are good for the blood, and cocoa polyphenol extracts are good for the gut. You need them both.

Polyphenol Purity
Just as like omega-3 fatty acids, the purity of polyphenols is critical for their use in high-dose applications.  The best indication of polyphenol purity is whether or not the polyphenol extract has been purified by column chromatography.  Try to look for those very limited number polyphenol extracts that have undergone such refining.  To date, only selected polyphenol extracts from the Maqui berry (a member of the blueberry family) meets this criteria.  Furthermore, such purified maqui extracts represent the highest levels of delphinidins available.

Although no cocoa polyphenol extracts are available that have been refined by column chromatography, a few products have been extracted by specialized organic solvents to remove much of inherent cadmium.  This is important as most crude cocoa polyphenols extracts (as well as cocoa powders and cocoa nibs) are naturally high in in the heavy metal cadmium.  Using these specialized solvent-based refining techniques can dramatically lower cadmium levels.  The only way to know if a cocoa polyphenol extract is low in cadmium is to check on the cadmium levels of the final product.  If that information is not posted on the website of the product, then assume the cadmium levels are probably too high.   As with omega-3 fatty acid concentrates, this is another example where refined if often better (and safer) than natural.

Polyphenol Extract Facts and Fantasies
Given the complexity of polyphenol science, it is quite easy for marketing hype to overwhelm scientific fact. Here is one statement that is constantly repeated as the truth: “Resveratrol is the primary polyphenol found in red wine.” First, that is simply not true. There are some fifty different polyphenols in red wine, and resveratrol is a minor polyphenol among them. The highest concentration of polyphenols in red wine come from a specific class of polyphenols known as anthocyanins. Anthocyanins are the primary polyphenols found in berries and grapes. Second, pure resveratrol is a highly astringent off-white powder. It is highly unlikely that a white powder is going to give red wine its color. Third, resveratrol is not very water-soluble, so very little of it will every reach the blood to activate AMP kinase. Finally, virtually all commercial resveratrol comes from the Japanese knotweed, which as its name implies is a weed that is highly invasive to crops. That kind of takes all of the mystique away from resveratrol and red wine, as well as resveratrol supplements. This is why resveratrol supplements may not be a very good choice to increase AMP kinase activity in your body.

If resveratrol in red wine isn’t the key to the health benefits, then what is? It certainly can’t be the alcohol since no one talks about the health benefits of vodka. Maybe it’s one of the other polyphenols found in red wine. The most likely candidate is a sub-class of anthocyanins known as delphindins. These unique polyphenols are everything resveratrol is not. First, delphindins are water-soluble (remember that wine is primarily water), meaning they can enter into the bloodstream. Second, purified delphinidin extracts have extensive clinical benefits ranging from reducing blood glucose levels to decreasing oxidative stress, both important factors in managing diabetes.  Third, they can be purified to high potency using column chromatography.

So, how do you get adequate levels of delphindins and begin to activate AMP kinase more effectively? You could drink a lot of red wine (about 56 glasses per day), but you can imagine there might be some health problems with that approach. Although red grapes contain some delphinidins, those levels are low compared to other fruits, in particular blueberries. Even with the blueberry family, there is a considerable variation in delphinidin content. American blueberries contain relatively low levels of delphinidins, bilberries (also known as Russian blueberries) contain higher levels, but the richest source of delphindins is the maqui berry (also known as the Patagonian blueberry). In fact, during the French wine crisis in the 1970s, tons of maqui berries were sent from Chile to France to blend with the weakened grapes to maintain the red color of the wine and thus save their red wine industry.

Research has shown that the delphinidins in purified maqui polyphenol extracts can easily enter the blood intact, thus they are more effective than other polyphenols to activate a wide number of gene transcription factors by increasing the activity of AMP kinase (see Appendix E for more details).  Increased AMP kinase activity is the final key necessary to complete the Resolution Response.

On the other hand, cocoa polyphenols are primarily composed of polyphenol polymers which are not water-soluble but can be broken down to individual polyphenols by the bacteria in the gut.  In this regard cocoa polyphenols are great for the gut.

What are Adequate Intake Levels for Polyphenols?
The answer depends on which benefit generated by activation of by AMP kinase you are trying to achieve. A general suggestion for water-soluble polyphenols (like maqui polyphenols) might be:

Benefit                                                           Polyphenol intake required   

Reduces oxidative stress                                    500 mg per day

Reduces inflammation                                        1,000 mg per day

Increase mitochondrial efficiency                    1,500 mg per day

For water-insoluble polyphenols (like cocoa polyphenols), a general suggestion might be:

Benefit                                                                   Polyphenols intake required

Gut health                                                             1,000  mg per day

Summary
Polyphenols have a remarkable range of physiological actions in both your cells to control your metabolism and in your gut to reduce the likelihood of a leaky gut and promote the growth of beneficial bacteria such as Akkermansia. Most importantly, polyphenols play a unique role in the final step of the Resolution Response by increasing the energy needed to repair damaged tissue. However, those repair benefits will be maximized only if you have first reduced diet-induced inflammation with the Zone Diet followed by the resolving of residual cellular inflammation with adequate levels of omega-3 fatty acids.  Only after those two stages of the Resolution Response are completed can you begin to repair damaged tissue (and that includes the gut wall) caused by prior diet-induced inflammation. This is the final step of the healing process of the Resolution Response, which can be greatly accelerated with the use of polyphenol extracts that can increase AMP kinase activity.  With that increase in AMP kinase activity comes a longer healthspan. This is why using purified polyphenol extracts can be considered gene therapy in the kitchen.