Inflammation is a crucial component of our metabolism that keeps us alive. It is our initial defense against microbial invasion or physical injury. However, unless we turn off that initial inflammatory response, it can become chronic low-grade inflammation below the perception of pain, which generates continuing tissue damage and accelerates aging. Your body needs to turn inflammation on and then turn it off when it is no longer required to maintain maximal metabolic efficiency.
Before I explain how each component of Metabolic Engineering® contributes to this process, let me define the three distinct types of inflammation: lipid-based, protein-based, and oxidative stress-based.
Let’s start with lipid-based inflammation. This type of inflammation consists primarily of hormones known as eicosanoids, which are released by cells as the first responders to injury. Although hormones are usually defined as being derived from a specific gland, in the case of eicosanoids, every cell in the body can make them. This means you have about 30 trillion eicosanoid-secreting glands.
The 1982 Nobel Prize in Medicine was awarded for the early understanding of how eicosanoids are made and why drugs such as aspirin work to inhibit their release. Eicosanoids include powerful pro-inflammatory hormones derived from the omega-6 fatty acid, arachidonic acid (AA). Eicosanoids derived from omega-3 fatty acid eicosapentaenoic acid (EPA) are weak pro-inflammatory hormones. However, EPA blocks the formation of eicosanoids derived from AA. This means that as EPA levels increase in the blood or a cell, the intensity of any inflammatory response induced by AA-derived eicosanoids will be moderated.
It was the 1982 Nobel Prize in Medicine that led me to change my medical research career from developing intravenous cancer drug delivery systems to developing nutritional systems that maintain improved control of the inflammation response. My challenge was to develop dietary interventions that could alter the balance of these hormones to moderate the initial level of inflammation. The key was controlling the balance of two other hormones (insulin and glucagon). As you can see, these metabolic pathways that control the inflammatory action of eicosanoids are complex.
Putting this all together was the starting point for developing the Zone diet that I discussed in my first book, The Zone, published 30 years ago. The Zone diet provided a superior approach to managing chronic low-level inflammation by reducing the use of anti-inflammatory drugs.
The next phase of my research on controlling lipid-based inflammation involved using high-dose omega-3 fatty acids (both EPA and DHA) to resolve inflammation. These fatty acids, when ingested in higher doses, enable the formation of another group of lipid-based hormones known as resolvins, which I described in my 2001 book, The OmegaRx Zone. Although DHA has no role in modulating eicosanoids, it is a key component in the synthesis of many resolvins. As to the exact mechanism by which resolvins turn off inflammation, it remains a matter of investigation; however, it appears to be mediated by cyclic AMP which then activates of AMPK (1).
Eicosanoids are the first responders, acting as a fire alarm to any microbial invasion or physical injury. The next phase is carried out by protein-based inflammatory mediators, which are the next group of compounds that take up the challenge of bringing the immune system into the battle. These proteins represent the second type of inflammation. The primary players in this phase of inflammation are protein-based compounds known as cytokines. Although these proteins are not typically considered hormones, they play a crucial role in the cellular signaling that directs immune cells to the site of existing inflammation. However, their synthesis is controlled by activation of the gene transcription factor known as NF-κB. The activation of NF-κB is inhibited by activation of the master regulator of metabolism, AMPK. Thus, AMPK is a key player in modulating cytokine levels.
The final class of inflammatory mediators is the enzymes that reduce oxidative stress. Oxidative stress is the result of the excess generation of free radicals. Under ideal conditions, when the levels of free radicals are increased, AMPK is activated (2). This activation of AMPK is the first step in activating another gene transcription factor, known as Nrf2. Once Nrf2 is activated, it causes the expression of various anti-oxidative enzymes that destroy the excess free radicals before they can cause damage to your DNA.
Now let’s return to how Metabolic Engineering® can activate each of these three seemingly diverse anti-inflammatory systems, starting with omega-3 fatty acid intake. It begins with an adequate intake of omega-3 fatty acids to achieve maximum control of lipid-based inflammation. Sufficient levels of EPA are required to reduce excess eicosanoid formation; however, both EPA and DHA are necessary to promote the formation of resolvins. The result is that chronic low-level inflammation is decreased. What is an adequate intake? Probably about 2.5 grams of EPA and DHA per day. Unfortunately, the average American consumes about 0.1 grams per day (3). To be even more precise, you need enough omega-3 fatty acid intake to reduce the AA/EPA ratio in the blood to reach a target goal between 1.5 and 3. The AA/EPA ratio in Americans is closer to 15 (4). The higher the AA/EPA ratio in the blood, the greater the level of chronic low-level inflammation in your body, and the more likely you are to develop a chronic disease and age at a faster rate.
However, the omega-3 fatty acids will have a limited effect on reducing cytokines. Fortunately, the Zone diet has a significant impact in this regard. The calorie restriction inherent in the Zone diet is the most potent way to activate AMPK. Once you activate AMPK, the activity of gene transcription NF-ⲕB is reduced. As a result, the levels of excess cytokines are correspondingly decreased. This is why the Zone diet is considered to be an anti-inflammatory diet.
Finally, polyphenols can reduce free radicals by activating Nrf2, but only if they can get into the blood. Polyphenols don’t directly activate Nrf2 but do so indirectly by activating AMPK. Unfortunately, most polyphenols have very low bioavailability, so their impact on reducing oxidative stress is often minimal. However, one of the few polyphenols that can directly enter the body is delphindins, which are a subclass of anthocyanins (5). Yet for maximum efficacy, even delphinidins need to be combined with the Zone diet to ensure there is adequate AMPK activity to activate the gene transcription factor Nrf2 sufficiently. It is only when Nrf2 is activated sufficiently that it will cause the expression of the necessary anti-oxidative enzymes to quench excess free radicals.
Thus, combining the adequate intake of omega-3 fatty acids, using the Zone diet, and select polyphenol concentrates rich in delphinidins into a consistent dietary system (i.e., Metabolic Engineering®) that allows you to control each of the three types of inflammation with precision is far greater than any drug. Used correctly, Metabolic Engineering® will enable you to maintain inflammation in a therapeutic zone, where it can perform its function when needed and then revert to a quiet state, waiting for the next insult to your body. The better you maintain inflammation in that zone, the longer and better you will live.
References
1. Aslam M, Ladilov Y. Emerging role of cAMP/AMPK signaling. Cells. 17;11:308 (2022) doi: 10.3390/cells11020308.
2. Auciello FR, Ross FA, Ikematsu N, Hardie DG. Oxidative stress activates AMPK in cultured cells primarily by increasing cellular AMP and/or ADP. FEBS Lett. 588:3361-3366 (2014). doi: 10.1016/j.febslet.2014.07.025.
3. Froyen E, Maarafi Z. The consumption of omega-3 fatty acids in American adults. Curr Dev Nutr. 6:902 (2022). doi: 10.1093/cdn/nzac067.022.
4. Harris WS, Pottala JV, Varvel SA, Borowski JJ, Ward JN, McConnell JP. Erythrocyte omega-3 fatty acids increase and linoleic acid decreases with age: Observations from 160,000 patients. Prostaglandins Leukot Essent Fatty Acids. 88:257-63 (2013). doi: 10.1016/j.plefa.2012.12.004.
5. Schön C, Wacker R, Micka A, Steudle J, Lang S, Bonnländer B. Bioavailability study of maqui berry extract in healthy subjects. Nutrients. 10:1720 (2018). doi: 10.3390/nu10111720.
