The Mediterranean Zone (21 page)

Although activation of PPAR-γ can inhibit the activation of NF-κB that starts the inflammation process, it can’t inhibit the inflammatory mediators (cytokines) that are released once NF-κB has caused the expression of inflammatory genes. Returning these inflammatory dogs of war to their barracks is done during the resolution phase of inflammation.

Inflammation doesn’t stop like the embers of a burning log dying out. It will continue unless reversed by an equally complex resolution response. This is driven primarily by a group of pro-resolution eicosanoids derived from omega-3 fatty acids called resolvins. Without adequate levels of omega-3 fatty acids in the diet, it is difficult to make adequate levels of resolvins. As a consequence, the soldiers of your immune response now start attacking normal tissue. This leads to long-term organ damage that, if severe enough, we call it chronic disease. My molecular definition of wellness is the maintenance of the balance of the initiation and resolution phases of inflammation in a tightly regulated zone.

One of the consequences of the increased release of inflammatory mediators is the activation of the killer cells (neutrophils and macrophages) of the innate immune system. These killer cells are the normally benign white cells of the circulatory system. However, they are quickly transformed into rogue killing machines once inflammatory mediators such as cytokines or eicosanoids activate them. One of the primary ways that these rogue warrior cells can attack microbial invaders is by the generation of free radicals, which act as localizing radiation. To minimize damage to normal tissue, another key safety valve to control the oxidative damage caused by these excess free radicals is to signal for more anti-oxidant enzymes to be produced. This is done by the interaction of polyphenols with the gene transcription factor Nrf2 that causes the increased synthesis of additional anti-oxidant proteins such as superoxide dismutase (SOD) and glutathione peroxides (GPX) to neutralize any continuing flow of excess free radicals
from the immune cells, which may not realize their mission is over and they are no longer needed.

If you want to control cellular inflammation, you have to decrease certain types of fats (omega-6 and saturated fats) in the diet as well as the hormones (such as insulin) stimulated by high-glycemic carbohydrates that can stimulate a hair-trigger inflammatory response by accelerating AA formation. You lower AA formation by eating a lot of non-starchy vegetables with limited amounts of fruits and using only fats low in omega-6 fatty acids (such as olive oil). At the same time, you have to increase the levels of omega-3 fats and polyphenols to be able to resolve the inflammation. If this sounds like the Mediterranean Zone, it is.

The molecular definition of cellular inflammation is an imbalance in pro-inflammatory responses and the resolution of inflammation leading to chronic low-level activation of inflammation.

There are two types of inflammation. The first type is classical inflammation, which generates easily observed inflammatory responses, such as heat, redness, swelling, pain, and eventually loss of organ function. The other type is cellular inflammation, which is below the perception of pain and is more deadly because it can linger unnoticed and unaddressed for years, if not decades, constantly damaging organ function. Cellular inflammation can be caused by either (1)
excess
AA formation that turns
on
the innate immune system, or (2) a
deficiency
of EPA and DHA that turns
off
an activated innate immune system. In either case, if these on-off commands are imbalanced, your body is at long-term risk of developing a chronic disease at an earlier age. Furthermore, increased cellular inflammation disrupts hormonal signaling networks throughout the body. This is the cause of hormonal resistance, and in particular insulin resistance. As a result, you gain weight, develop chronic disease more rapidly, and age faster.

Anti-inflammatory nutrition is based on the ability of certain nutrients to reduce the activation of NF-κB. The most effective way to lower the activation of NF-κB is to reduce the levels of AA in the target cell membrane,
reducing the formation of leukotrienes and hydroxylated fatty acids, which can activate NF-κB. Following the Mediterranean Zone to reduce insulin levels coupled with the simultaneous lowering of the intake of omega-6 fatty acids is the primary lifelong dietary strategy to achieve and maintain a healthy, balanced inflammatory response.

Another effective dietary approach (and often easier to comply with) to reduce cellular inflammation is the enhancement of the resolution process of inflammation. This can be accomplished by dietary supplementation with adequate levels of purified high-dose fish oil rich in omega-3 fatty acids, such as EPA and DHA. Taken at high enough levels, these omega-3 fatty acids will lower AA levels somewhat (EPA more than DHA because it is more structurally similar to AA), but also dramatically increase EPA levels, which leads to increased resolvin production. The impact of this dietary change is reflected in the AA/EPA ratio in the blood (and therefore in the cell membranes of your various organs). This will have several anti-inflammatory benefits. First, a low AA/EPA ratio in the blood will reduce the likelihood of the formation of inflammatory eicosanoids derived from AA that can activate NF-κB. This is because leukotrienes derived from AA are pro-inflammatory, whereas those leukotrienes from EPA are non-inflammatory. Second, the increased intake of both EPA and DHA can activate the anti-inflammatory gene transcription factor PPAR-γ inside the cell as well as decrease the binding of saturated fatty acids to TLR-4 on the cell surface. Third, and most important, is the increased levels of resolvins derived from EPA and DHA will dramatically accelerate the resolution process of inflammation. This illustrates the multi-functional roles that omega-3 fatty acids have in controlling cellular inflammation.

The third dietary intervention to reduce diet-induced inflammation is the adequate intake of dietary polyphenols. Polyphenols are powerful anti-oxidants that at high enough levels reduce the formation of reactive oxygen species (ROS) that are generated by the conversion of dietary calories into chemical energy as well as the ROS generated by activated immune cells, such as neutrophils and macrophages. Excess ROS can activate NF-κB. Polyphenols can also inhibit the activation of NF-κB by activating the anti-inflammatory gene transcription factor (PPAR-γ), making polyphenols both anti-oxidants and anti-inflammatory compounds.

Finally, the least effective dietary strategy—but still a useful one—is reducing the intake of saturated fat. (The American Heart Association was
partially right about reducing the intake of saturated fat, but for the wrong reason.) This is because saturated fatty acids will cause the activation of the TLR-4 receptor in the cell membrane. (Remember this toll-like receptor binds to saturated fats and activates NF-κB.)

Obviously, the greater the number of these dietary strategies that you employ in your daily life, the greater their overall effect in reducing diet-induced inflammation. The easiest way to make them all come together at the same time is by following the Mediterranean Zone on a lifetime basis.

Since cellular inflammation (chronic activation of NF-κB) is confined to the cell itself, there are no blood markers that can be used to directly measure it. However, there are indirect ways to measure cellular inflammation. The commonly used marker of high-sensitivity C-reactive protein (hs-CRP) is not a very good indicator because it is highly sensitive to slight increases in bacterial infection and only increases after long-term activation of NF-κB. On the other hand, the AA/EPA ratio in the blood indicates that a tipping point has been reached that is likely to activate NF-κB in the cells. Consider the AA/EPA ratio to be your early-warning system for increased cellular inflammation—an elevated level of the AA/EPA ratio often precedes the development of elevated hs-CRP by several years, if not decades.

Ultimately you want to control levels of cellular inflammation to retard the development of chronic disease and, in the process, slow down the aging process.

Under ideal conditions, the initiation phase of inflammation is counter-balanced by the resolution phases of inflammation. This can be measured by the AA/EPA ratio in the blood. If the AA/EPA ratio is high, this indicates that your ability to resolve inflammation is compromised. The body has a fail-safe mechanism to solve this problem. It’s called fibrosis. Think of fibrosis as burying toxic waste. If your body can’t adequately resolve the inflammatory process, then it can just bury it by cementing it over with scar tissue. You contain the inflammation, but you damage that area of the organ. Scar tissue on the surface of the skin is a visual indication of what is taking place during fibrosis inside your body. Observing internal scarring is more difficult, but the loss of organ function that comes with extensive
fibrosis is not. Atherosclerotic plaques are the result of fibrosis, for instance. If those plaques are not completely encased by a fibrous cap enriched in calcium, they can rupture, leading to sudden cardiac death. Or if you have too much scar tissue in the heart, it fails to function, and we call it heart failure. Cirrhosis of the liver is the result of extensive fibrosis. If the liver doesn’t function because of extensive fibrosis, it is called liver failure, requiring a lifetime of dialysis or a liver transplant. Chronic obstructive pulmonary disease (COPD) is a result of fibrous lung tissue. The list goes on. The reason for fibrosis is the failure of the resolution response to work properly in the first place. The more fibrosis you have in the body, the less effectively your organs work and that is what we call aging.

It is now becoming recognized that virtually every chronic disease condition starts with either an increased initiation or a reduced resolution of the inflammatory response. In fact, it might be more correct to state that chronic disease is not
caused
by inflammation, but is really a
consequence
of the lack of adequate resolution. The more these two separate parts of the inflammatory response are imbalanced, the greater the production of cellular inflammation. The better able we are to control cellular inflammation, and the longer we put off the development of chronic disease, the longer and better you are going to live. The Mediterranean Zone provides a clear path to that goal.

T
he definition of
obesity
is “the accumulation of excess body fat,” not excess weight. In practical terms, we usually identify obesity by how we look stark naked in the mirror. However, it is the excess fat accumulation in our organs that we can’t see that ultimately determines how detrimental that obesity will be to our future health. This is called lipotoxicity and is the first step toward developing diabetes. But first let’s start with two very separate questions: (1) How do we get fat? (2) Why do we get fat?

Although the diet book industry is devoted to weight loss, no one seems to be quite able to describe how we actually get fat. I described the process in greater detail in my book
Toxic Fat,
but here is a short summary.

Your fat cells are the only cells in the body that can safely store fat; and if they are healthy fat cells, that is exactly what they will do. By removing excess fatty acids from the bloodstream, your fat cells prevent lipotoxicity. This is the scientific term for when fat goes to all the wrong places, such as
your liver, your muscles, or your heart cells, for example. As I stated earlier in this book, insulin is the central hormonal hub of your metabolism. Because high levels of lipids in the blood are toxic, insulin plays a key role in removing them and storing them safely in your fat calls. How insulin aids in helping your fat cells to remove excess blood fat is a little more complicated than simply saying “insulin makes you fat.”

Your fat cells are sensitive to insulin, as it is needed to increase the transport of glucose from the blood into your fat cells. Once in the fat cells, the glucose is converted to glycerol, which by itself will not remove any excess fat from the blood. However, insulin also can increase the release of free fatty acids from lipoproteins passing by the fat cells by the stimulating enzyme (lipoprotein lipase) that sits at the surface of the blood vessels that surround the fat cells. This increases the amount of free fatty acids, but these require fatty acid binding proteins to transport the newly released fatty acids into the fat cells. The production of those fatty acid binding proteins is also stimulated by insulin. Once you have both glycerol and fatty acids together within the fat cell, they can recombine to form triglycerides for long-term safe storage. The more fat and carbohydrates (especially high-glycemic carbohydrates that stimulate insulin secretion) you consume, the more fat you will store in the fat cells. This is how high insulin levels make you fat. In this case, insulin acts as a safety hormone to prevent a lipid overload in the bloodstream.

When you are not eating (such as during sleep), the fat storage process in healthy fat cells begins to reverse itself. As insulin levels drop, an enzyme in the fat cells splits the stored triglycerides back into fatty acids and glycerol to be released into the bloodstream. The fatty acids go to other cells throughout the body to be converted into chemical energy (that is, ATP) in their mitochrondria (these are the parts of the cell that convert dietary calories into ATP) to get you through the starvation period, and the glycerol is converted into glucose for the brain. Under normal conditions, when fat cells are healthy, your adipose tissue acts as a bank. You make deposits during the day and withdrawals at night. Of course, if you are maintaining high levels of insulin all the time, then you are inhibiting the key step required to release stored fat to be used as energy. This is why high levels of insulin keep you fat.