The Mediterranean Zone (24 page)

However, the real cause of mortality from heart disease is not lipid accumulation, but the rupture of the atherosclerotic plaque. The primary culprits are soft vulnerable plaques. They are called soft because they have not been encased in a thick fibrosis cap rich in calcium that makes it difficult for a hard plaque to rupture. These vulnerable soft plaques can’t be detected with scanning techniques such as CAT scans that easily pick up calcium deposits in the hard plaques. As a result, the soft plaques are all but invisible to CAT scans. Since they have no fibrous cap, they can easily rupture if the levels of cellular inflammation within them become too elevated. The ruptured plaque releases cellular debris that causes rapid formation of a clot in the artery that causes the stoppage of blood flow and often results in sudden cardiac death.

Strokes can be viewed as “brain attacks” because cerebral arteries develop the lesions as opposed to the cardiovascular arteries. While the location of the soft vulnerable plaques may be different in a different area (the cerebral artery as opposed to the vascular system), the molecular mechanism behind their development is similar as in heart disease.

Cancer is often viewed as genetic disease; however, I believe it can be better understood as a metabolic and inflammatory disease. Rarely will the primary tumor cause death. However, if the primary tumor metastasizes to other organs, the eventual outcome for the patient is often bleak. What mediates that metastasis is inflammation, and in particular inflammatory eicosanoids derived from AA. These eicosanoids (especially PGE
₂
) depress the local inflammatory responses that would otherwise help orchestrate the destruction of the cancer cell, and other eicosanoids (hydroxylated fatty acids such as 12-HETE) derived from AA help the circulating tumor cells to get a foothold in a new location. In fact, cancer is often described as “a wound that never heals.” That is also a good definition of unresolved inflammation. One of the inflammatory factors released by the activation of NF-κB is a group of enzymes known as matrix metalloproteinases (MMP) that break down the collagen matrix, making it easier for a roaming tumor cell in the blood to enter a new site. Both events are enhanced by increased levels of AA in the cancer cell. The excess AA is transformed into leukotrienes that increase the activity of NF-κB that causes the synthesis of more
MMP and the excess AA is also the substrate required to make hydroxylated fatty acids and PGE
₂
, that facilitates metastasis.

The other factor that drives tumor cells is increased blood glucose levels. Tumor cells have a very limited capacity to oxidize fats for energy. They rely primarily on glucose to fuel their energy needs, so reducing blood glucose levels is an excellent metabolic strategy for managing tumor growth. In addition, high levels of blood glucose will increase insulin levels (especially in the presence of insulin resistance). Insulin is a growth factor and has significant cross-reactivity with another hormone—insulin-like growth factor, or IGF—that is a strong hormonal driver of tumor cell growth. This is not to say that genetic factors are not important in cancer, but only to note that you have a great ability to control your metabolism by an anti-inflammatory diet to make it much more difficult for tumors to grow and metastasize.

Many of the chronic diseases that are the result of immunological disturbances can be broken down into two categories: conditions driven by fibrosis, and those driven by unresolved inflammation.

Chronic pulmonary obstructive disease (COPD) has quickly risen to be the third leading cause of death after heart disease and cancer in the United States. Obviously initiated by pulmonary inflammation, it ends with loss of lung function caused by extensive fibrosis as a result of lack of resolution of the inflammation response. With COPD, you eventually require supplemental oxygen to maintain minimal oxygen levels in the blood. Other chronic diseases that fall into this category include liver failure (which requires a transplant) and kidney failure (which requires constant dialysis). All three diseases can be considered examples of failure of the resolution process and forcing that particular organ into the fallback strategy of scar tissue formation. With time, repeated inflammatory attacks leads to further loss of organ function.

Other immunological diseases, such as arthritis, systematic pain (such as fibromyalgia), gut disorders (Crohn’s disease and ulcerative colitis), allergies, asthma, and a wide number of other immunological disorders can also be considered as examples of unresolved resolution, but without the fibrosis. These diseases are usually treated with constant application of anti-inflammatory drugs to take the place of the more optimal approach of the resolution of inflammation in the first place.

Finally, there are the neurological diseases, which, like immunological
conditions, can be broken down into two distinct groups. The first is continued neuroinflammation without resolution. Diseases in this category include multiple sclerosis, Parkinson’s, and Alzheimer’s. The second category includes those neurological conditions that are the result of disrupted neurotransmitter communication between cells. You might consider these to be examples of neurotransmitter resistance, and these conditions would include depression, ADHD, and anxiety. As usual, the likely suspect in triggering these conditions is increased cellular inflammation.

This very brief overview suggests that the lack of inflammatory resolution may really be the root cause of most chronic diseases. Without adequate resolution, inflammation continues unabated at low chronic levels or the body resorts to an inferior option of fibrosis to reduce or contain the inflammation at a localized level. The primary treatment for reducing low-level cellular inflammation is not a drug, but an anti-inflammatory diet such as the Mediterranean Zone. The more you use the Mediterranean Zone as your primary drug of choice, the less you will need to rely upon pharmaceuticals to control the symptoms of chronic cellular inflammation.

T
he body is constantly renewing itself. Old or damaged tissue is being broken down, and new tissue is being made to take its place. If the old tissue is being broken down at a faster rate than new tissue is replacing it, then that mismatch in tissue renewal can be viewed as aging.

We can see the physical signs of aging in various locations in the body—the skin, the hair, bone loss, loss of muscle mass, increase in fat accumulation, and the loss of vision. What links all of these is increased cellular inflammation. So let’s look at each of these visible signs of aging, and see what is really happening under the surface.

One of the first signs of aging is the loss of taut, plump, youthful skin. For most people, the appearance of wrinkles is the most disturbing sign of aging. Essentially, wrinkles can be best understood as biological potholes on the surface of the skin. They are the result of two factors: (1) the loss of fat in the dermis of the skin that thins the skin and (2) the breakdown of the collagen matrix that gives the skin its structural support. The result of this collagen degradation is a disorganized collagen fiber structural
network. When coupled with the lack of dermal fat, the skin wrinkles. (This is why one of the hottest areas in dermatology is the injection of fat cells harvested from liposuction of one’s own adipose tissue.) The ultimate cause of collagen destruction is the increased production of enzymes known as matrix metalloproteinases (MMP). You shouldn’t be surprised that generation of these collagen-degrading proteins is a result of NF-κB activation. Externally, UV radiation increases the free radical formation that causes the activation of NF-κB. Sunscreens are good for blocking UVA radiation, but not as useful in stopping UVB radiation. Internally, an anti-inflammatory diet can inhibit the activation of NF-κB by both types of UV radiation. This is why the anti-inflammatory Mediterranean Zone, which is rich in polyphenols, can significantly reduce ROS (reactive oxygen species) production by UVB radiation as well as activating the gene transcription factor Nrf2, producing the increased synthesis of powerful anti-oxidant enzymes. It is also known that high levels of omega-3 fatty acids can inhibit the synthesis of MMP. Thus the Mediterranean Zone enriched with high-dose omega-3 fatty acids may represent the best “anti-aging prescription” for younger looking skin.

No one is quite sure what causes the loss of dermal fat. I suspect it may be due to insulin resistance inhibiting the action of insulin to keep fat stored in the dermal fat cells, thus reducing insulin resistance systemically, and helping to maintain dermal fat levels. The one thing I know for certain is that as you lose dermal fat, your sensitivity to cold significantly increases as you are losing a powerful thermal barrier, which would help retain your core temperature. This is why as people age, they often spend more time looking at travel brochures for potential winter travel in Florida, the Caribbean, and Mexico.

Hair loss is one of the facts of aging. Much of hair loss is genetically controlled, but there is an indication that those genetic predispositions may be altered by eicosanoids. In particular, the prostaglandin PGD
₂
derived from AA inhibits hair growth. Another synthetic eicosanoid used to treat glaucoma can stimulate eyelash growth and is in preliminary studies for stimulating hair growth. Again, it is a matter of eicosanoid balance.

The loss of hair color is another obvious sign of aging. The latest research indicates that the graying of hair is due to the increased generation
of ROS within the hair follicle. The best way to reduce ROS is to make sure you have high levels of polyphenols in the diet. Since ROS activates NF-κB, an anti-inflammatory diet coupled with high dose omega-3 fatty acids should also support maintaining hair color for longer periods of time.

Therefore, the best eicosanoid modulating and anti-oxidant “drug” for the hair may be the Mediterranean Zone coupled with high-dose fish oil.

You can live with wrinkles and gray hair, but loss of bone mass is another story. There are two types of cells in the bone: the osteoblasts that build bone and the osteoclasts that degrade and resorb bone. We tend to think that bone loss is due to lack of calcium, but in reality it is primarily a consequence of increased cellular inflammation that activates the osteoclasts. In animal models it has been shown that increasing the levels of omega-3 fatty acids provides a significant improvement in bone density. In particular, the resolvin derived from EPA (RvE1) has been shown to be effective in preventing bone resorption.

One reason that muscle mass decreases with age is the lowered levels of testosterone and growth hormone, which are the anabolic factors needed for maintenance of muscle for both men and women. This leads to sacropenia (loss of muscle mass) and eventually frailty. Another factor leading to loss of muscle mass is the increase in pro-inflammatory cytokines that are produced as the result of increased cellular inflammation. Obviously, there is a continued need for exercise as a stimulus for creating new muscle mass. Even with the lowered levels of testosterone and growth hormone that comes with aging, this loss of muscle mass may be lessened by the reduction of inflammatory cytokines.

If you want to preserve muscle mass as you age, then ensuring that you have adequate protein intake and simultaneously reducing cellular inflammation are two dietary factors you can control. The Mediterranean Zone does it automatically for you. However, you still need to exercise on a daily basis to maintain testosterone and growth hormone levels. The greater the intensity of the exercise in short bursts (interval training), the better the results.

It’s one thing to lose fat in your skin, but it is much more disturbing to gain fat in your abdomen and hips. This usually begins in your thirties even if your exercise and diet doesn’t change that much from what it was in your twenties. This occurs because the levels of testosterone and estrogen—in both men and women—are dropping. Both of these hormones are very effective in preventing the accumulation of stored body fat in both males and females. Furthermore, as estrogen levels drop, insulin levels begin to increase, driving fat into the adipose tissue as opposed to diverting it to the peripheral tissues to make more ATP. Couple these facts with increasing insulin resistance caused by increased diet-induced inflammation and fat accumulation becomes a fact of aging. The best way to rectify the situation is calorie restriction without hunger or malnutrition. This is why if you want to look twenty years younger, your first step may be to lose 20 pounds of excess fat. If you are not overweight, then add 5 pounds of new muscle mass. The Mediterranean Zone provides such a pathway to reach either goal.

Vision loss is another obvious sign of aging. The primary cause of blindness after the age of 50 is age-related macular degeneration (AMD). The underlying cause of AMD is inflammation in the retina. In recently published work, I demonstrated that high-dose purified omega-3 fatty acids can reverse dry AMD (90 percent of all AMD is dry AMD), which is rather remarkable since there is no prescription drug capable of doing so. Subsequent analysis of the data demonstrates a strong relationship between the AA/EPA ratio and the gain of vision. For those with an AA/EPA ratio at 1.5, their gain of vision is twice as great as those with an AA/EPA ratio of 2.5. Considering that the average American has an AA/EPA of approximately 20, this means significant supplementation of omega-3 fatty acids would be needed to reduce cellular inflammation in the eye—a small price to pay for regaining your eyesight.

Any discussion of aging must include gene transcription factors, especially those that are important in metabolism. The two primary ones involved in aging appear to be mTOR (mammalian target of rapamycin) and AMP
kinase. mTOR is the gene transcription factor that turns on growth and is directly activated by the amino acid leucine. It is essential for maintaining muscle mass. Unfortunately, it also stimulates tumor growth. AMP kinase is an energy sensor of ATP levels in the cell and acts as the master genetic switch of metabolism. If ATP levels are low, this enzyme is activated to recycle AMP back into ATP. At the same time it improves the efficiency of the general metabolism by slowing the anabolic process of tissue rebuilding that requires a lot of energy so that more ATP can be generated with fewer calories to maintain the functioning of existing cells. At the molecular levels, it is the constant balancing act of these two gene transcription factors that determines our rate of tissue renewal and the speed of aging.