The Mediterranean Zone (25 page)

Activation of mTOR for new protein synthesis is a consequence of the interaction of leucine to stimulate mTOR, coupled with the need for adequate insulin to drive nutrients into cells to provide the raw materials for new protein synthesis. On the other hand, AMP kinase can be activated by calorie restriction and polyphenols. Both act on the SIRT1 gene that is important in slowing the aging process. All of these factors are under your control. The Mediterranean Zone provides a blueprint to continually balance these two opposing gene transcription factors and thus control the rate of aging.

Of course the primary problem with aging is the development of chronic disease (described in Appendix D), which robs us of our quality of life. So whether it is the slowing down of the development of chronic disease or simply reducing the physical signs of aging, both goals lead back to the reduction of diet-induced inflammation.

W
e have many clinical markers of illness but relatively few markers of wellness. Ultimately, true health reform comes when patients take increased responsibility for their health by maintaining a state of wellness. The number-one factor within a patient’s control is their diet because of its ability to manage cellular inflammation. However, with the rise of the industrialization and globalization of food, this is becoming a more difficult prospect on a worldwide level. Nonetheless, as I have shown throughout this book, it is actually quite easy to take control of your health care future by being in the Zone.

Being in the Zone is determined by clinical evidence, not hope. Your blood chemistry will tell you with absolute clarity whether you are in the Zone, and if not, you will have a clear indication from your test results what you have to do from a dietary standpoint to get there.

Broadly speaking, there are three distinct metabolic measurements that determine if you are in the Zone: (1) your levels of cellular inflammation, (2) your long-term control of blood sugar levels, and (3) your levels of insulin resistance. This is not a multiple-choice test.
Only when all three markers are in the appropriate ranges can you be considered to be in the Zone.
Unfortunately, when we use those criteria, it appears that less than 1 percent of Americans can be considered to be well.

Since the Zone is about maintaining a healthy inflammatory response, your levels of cellular inflammation are an exceptionally important clinical marker.

Unfortunately, the most commonly used diagnostic marker of inflammation is C-reactive protein (CRP), which is simply not very reliable. CRP is a marker of long-term activation of NF-κB. Very few of the inflammatory mediators expressed in the cell by NF-κB can reach the blood. Most inflammatory mediators released by NF-κB act locally on nearby cells and enter the bloodstream with difficulty. Only one, IL-6, seems to have much success. Nonetheless, even IL-6 must eventually reach a very high level in the blood to interact with the liver to produce CRP. Since CRP is a more long-lived marker in the blood, it is much easier to measure than the more immediate inflammatory products (IL-1, IL-6, TNF, and COX-2 enzymes) produced by NF-κB activation. However, being easier to measure doesn’t necessarily translate into a better clinical marker of cellular inflammation. In fact, an increased AA/EPA ratio in the blood often precedes any increase of C-reactive protein by several years, if not decades. An elevated AA/EPA ratio indicates that NF-κB is at the tipping point of chronic activation, and the cells in every organ in the body are primed for increased genetic expression of a wide variety of inflammatory mediators. The measurement of CRP only indicates that NF-κB has been activated for a considerable period of time. This is why the AA/EPA ratio in the blood is your ideal early-warning beacon that your wellness is eroding. The other trouble about CRP as a clinical marker of cellular inflammation is that very slight bacterial infections can cause it to become elevated. This makes it unreliable as a marker of chronic cellular inflammation. This is why if your CRP is elevated, it is usually recommended to retake the test in a few weeks to make sure it wasn’t caused a slight bacterial infection.

If the AA/EPA ratio in the blood is the best marker of your ongoing ability to control cellular inflammation, then what should your levels be? After
thousands of blood tests in Americans and data reported from Italians and Japanese, I can give you some guidelines:

Ideally, you want to have your AA/EPA ratio between 1.5 and 3. As the AA/EPA ratio increases, so does your level of cellular inflammation. The average AA/EPA ratio in Americans is about 20. This is why American health care is crumbling—not from a lack of resources, but because Americans have a consistently and significantly high rate of cellular inflammation.

The fastest way to reduce the AA/EPA ratio is to take supplemental omega-3 fatty acids. The more you follow the Mediterranean Zone, the lower the levels of omega-3 fatty acids you will need since the Mediterranean Zone greatly restricts the intake of omega-6 fatty acids and moderates insulin levels that are both needed to produce AA. Adding supplemental omega-3 fatty acids will speed the process considerably so that within thirty days of following the Mediterranean Zone, you will begin to see a significant change in the AA/EPA ratio.

There are a number of private laboratories that do such AA/EPA testing. Some of these are listed below:

OmegaQuant (
www.omegaquant.com
)
MetaMatrix (
www.metametrix.com
)
Zone Diagnostics (
www.zonediagnostics.com
)

The prices range from $75 to $200 for the test. However, this may be the most important investment you can make in your future health.

The second marker of wellness is your level of glycosylated hemoglobin. Glucose is a very reactive compound that can link to proteins creating what is called advanced glycosylated endproducts (AGE). The formation of these AGE compounds comes from the Maillard reaction that occurs any time you have glucose, protein, and heat mixed together in a test tube. The same chemical reaction occurs inside your body if glucose levels become elevated in the blood. The resulting glycosylated proteins are sticky and end up in all the wrong places, such as the kidney, the eye, and the heart. Actually, it is even more complicated than that since there are receptors for these glycosylated proteins (known as RAGE) that if activated, initiate inflammatory responses through activation of NF-κB. RAGEs are similar to toll-like receptors in that they are based on pattern recognition. Although all proteins can become glycosylated in the presence of blood glucose, the most studied is glycosylated hemoglobin known as HbA
₁
c. Since hemoglobin is a long-lived protein, the levels of HbA
₁
c give an excellent marker of the long-term levels of glucose in the blood. The higher the HbA
₁
c levels, the more AGE products you have in the blood to interact with their receptors (RAGE), thus continually flaming cellular inflammation by activating NF-κB. To make matters worse, the more you activate NF-κB, the more RAGE receptors are synthesized. The result is a fast-forwarding of cellular inflammation. This is why the levels of RAGE are strongly associated with increased diabetes, heart disease, cancer, and Alzheimer’s, all inflammatory diseases.

What are the levels of glycosylated hemoglobin that are consistent with longevity? These levels (expressed in percent of the total red blood cells) are shown below:

Shouldn’t a lower percentage of glycosylated hemoglobin be even better? Not necessarily, since mortality begins to increase if glycosylated
hemoglobin levels are too low. Low levels may indicate that the brain is not getting enough glucose to perform optimally. Like all markers of wellness, there is a zone.

The best way to reduce AGEs and RAGEs is simply not to consume a lot of carbohydrates, especially grains and starches, since they are composed of long polymers that are pure glucose. The best dietary solution to reduce AGE formation is to eat a lot of non-starchy vegetables The more non-starchy vegetables that you use as your carbohydrate source in your diet, the better the long-term blood sugar control. Since the lifetime of the red cells is 120 days, give yourself about four months to see a significant difference. Another dietary approach is to reduce the activation of NF-κB by consuming lots of polyphenols and omega-3 fatty acids. This is exactly what following the Mediterranean Zone accomplishes.

The final marker of wellness is the degree of insulin resistance in your body. A primary function of insulin is to reduce blood glucose levels by driving glucose into its target cells. (The brain requires a lot of glucose, but it doesn’t require insulin for the uptake of glucose into the brain.) Insulin resistance is caused by cellular inflammation interfering with the signaling that occurs when insulin binds to its receptor on the surface of the cell and disrupts the transmission of the signal into the cell. It’s as if the insulin wasn’t present in the first place.

The three major organs that are responsive to insulin interacting with its receptor are the adipose tissue, liver, and muscles (including heart muscles). Although the first place that insulin resistance starts is usually in your fat cells, the earliest clinical indication that insulin resistance is spreading is found in your liver.

The liver is the primary manufacturing site for taking in fats and repackaging them in the form of lipoproteins for delivery to peripheral tissues. Insulin resistance disrupts this lipid repackaging process. Triglyceride levels rise, high-density cholesterol levels decrease, and low-density lipoproteins become smaller, more dense, and more atherogenic (more likely to increase the formation of plaques in the arteries). All of these risk factors increase the likelihood of developing cardiovascular disease. The reason that these small dense LDL particles are atherogenic is that it appears
they are more easily oxidized in the blood. This is why the levels of oxidized LDL are far more predictive of future heart disease than total LDL levels are.

As insulin resistance (really cellular inflammation) spreads to the muscle, the glucose in the blood stays elevated, increasing the production of more glycosylated proteins (AGE) that increase inflammation throughout the body.

The best way to measure insulin resistance is by using a euglycemic insulin clamp, which is an extremely complex procedure done only under research conditions. The best surrogate marker of insulin resistance is the ratio of triglycerides (TG) to high-density lipoprotein (HDL) cholesterol in the blood. The higher the TG/HDL ratio, the greater the level of insulin resistance in the liver.

So what are good levels of the TG/HDL ratio? These are shown below:

You usually find a TG/HDL ratio of less than one in elite athletes or people who follow the Mediterranean Zone. The average American has a TG/HDL ratio of 3.5, indicative of developing widespread insulin resistance. By the time the TG/HDL is greater than 4, you have metabolic syndrome (pre-diabetes) or fully developed type 2 diabetes.

An alternative method of determining insulin resistance is the levels of fasting insulin. This is a more expensive test than the TG/HDL ratio so insurance companies don’t like to reimburse it. If you are able to get such a test, here are the numbers you are looking for in terms international units per ml (IU/ml).

Since insulin resistance is the result of cellular inflammation, by following a strict Mediterranean Zone dietary program supplemented with purified omega-3 fatty acids and polyphenols, you can expect to see significant changes within thirty days.

Once you are in the Zone, your challenge is to stay there for a lifetime. These markers of wellness will provide continued clinical sentinels in the blood to alert you if you are moving out of the Zone. The correction to get back into the Zone is easy. Just follow the dietary instructions in this book.

H
ow do you measure the levels of polyphenols in a food? The easiest indirect way is to determine the ORAC (oxygen radical absorption capacity) value. The technology to measure these values was developed in the 1990s to evaluate the anti-oxidant capacity of various foods. Although the ORAC value is related to the polyphenols found in a food, it doesn’t totally distinguish between polyphenols and other anti-oxidants in a particular food. To be totally useful, ORAC values should be further refined to measure the levels of anti-oxidant potential relative to the levels of absorbable carbohydrate (total carbohydrates minus fiber) in a food. Whole grains have good ORAC levels, but very high levels of absorbable carbohydrate levels relative to fruits and vegetables. The extra carbohydrate will significantly impact insulin levels, reducing the benefits of the associated polyphenol in that food. Therefore the higher the ORAC/gram of absorbable carbohydrates, the greater the impact that food ingredient will have on reducing cellular inflammation.