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The second time in your life during which the activity of this enzyme begins to decrease is after the age of 30. Eicosanoids are critical for successful reproduction. Since the primary child-bearing years for women are between the ages of 18 and 30, it makes good evolutionary sense to start turning down the activity of a key enzyme needed to make the precursors of eicosanoids required for fertility after age 30.
The delta-6-desaturase enzyme can also be inhibited by viral infection. The only known anti-viral agents are "good" eicosanoids such as PGA1 because of their ability to increase cyclic AMP levels that keep viral replication under control. On the other hand, if you are a virus, then your number-one goal is to inhibit the formation of this type of eicosanoid. This is exactly what many viruses do by inhibiting the delta-6-desaturase enzyme. By doing so, the virus has devised an incredibly clever way to circumvent the body's primary anti-viral drug (i.e. PGA1).

The final factor that can decrease the activity of delta-6-desaturase is the presence of two types of fatty acids in your diet; trans fats and Omega-3 fats. Trans fatty acids don't exist naturally but are produced by food manufacturers. They are essential Omega-6 fatty acids that have been transformed by a commercial process (known as hydrogenation) into a new spatial configuration that is more stable to prevent oxidation. The increased stability of these fatty acids makes them ideal for processed foods, but also makes trans fatty acids strong inhibitors of the delta-6-desaturase enzyme. Trans fatty acids occupy the active site of the delta-6-desaturase enzyme, thus preventing the formation of the activated essential fatty acids required for eicosanoid synthesis. In essence, trans fatty acids can be viewed as anti-essential fatty acids because of their inhibition of eicosanoid synthesis. This may be the reason why they are strongly implicated in the development of heart disease. How do you know if a food product you're consuming contains trans fatty acids? Look for the word "partially hydrogenated vegetable oil" on the label. If it is there, then you know the food contains trans fatty acids. Surprisingly, Omega-3 fats can also inhibit the delta-6-desaturase enzyme activity in producing GLA since short-chain Omega-3 fatty acids such as alpha linolenic acid (ALA) preferentially bind to the enzyme thus decreasing GLA synthesis, and long-chain Omega-3 fatty acids such as DHA act as feedback inhibitors of the enzyme.

The journey toward becoming an eicosanoid is still far from over after passing this first hurdle of making GLA. Once GLA is formed, it is rapidly elongated into dihomo gamma linolenic acid (DGLA), which is the precursor to many of the "good" eicosanoids. However, DGLA is also the substrate for the other rate-limiting enzyme in essential fatty acid cascade in the chart above. That enzyme is called delta-5-desaturase. The activity of this enzyme ultimately controls the balance of "good" and "bad" eicosanoids thus making it the primary target to alter its activity by your diet if your goal is to treat chronic disease and promote wellness.

This is because the end product that the delta-5-desaturase enzyme that produces from DGLA is arachidonic acid (AA). DGLA is the building block of many of the "good" eicosanoids, whereas AA is the building block of "bad" eicosanoids. Thus excess amounts of AA can be one of your worst hormonal nightmares. Ultimately, it is the balance between DGLA and AA in every one of your 60 trillion cells that determines which types of eicosanoids you will produce. You need some AA to produce some "bad" eicosanoids, but in the case of excess production of AA, the balance of eicosanoids will shift toward accelerated aging and chronic disease.

Some of the Eicosanoids Derived from Arachidonic Acid

Arachidonic Acid (AA)

COX 5-LOX 12 and 15 LOX

PGH2 TXA2 LTB4 12-HETE Lipoxin

PGD2 PGI2
LTBC4 15-HETE
PGJ2 PGF2a PGE2
PGB2 LTBD4
PGA2
LTBE4

Many of these eicosanoids derived from arachidonic acid can be considered to be "bad" because they promote inflammation (PGE2 and LTB4) and decrease blood flow (TXA2). In addition, the inflammatory "bad" eicosanoids can also promote the release of other pro-inflammatory cytokines.

While there is bewildering complexity of eicosanoids from ararchidonic acid, there are a very limited number of eicosanoids that come from dihomo gamma linolenic acid (DGLA) as shown below

Eicosanoids from DGLA

Dihomo Gamma Linolenic Acid (DGLA)

COX LOX

PGH1 15-OH Triene

PGE1

PGA1

The primary eicosanoid derived from DGLA is PGE1, one of the most highly studied "good" eicosanoids as it a very powerful vasodilator and inhibitor of platelet aggregation. It also reduces the secretion of insulin and increases the synthesis of wide variety hormones that normally decrease during the aging process. PGE1 is able to achieve these diverse functions because it causes an increase in cyclic AMP production. PGA1 is the most powerful suppressor of viral replication, especially HIV transcription, as well as inhibiting nuclear transcription factor NFkappaB necessary for synthesis of a wide variety of pro-inflammatory cytokines. And finally the 15-LOX enzyme can convert DGLA into a powerful inhibitor of the 5-LOX enzyme that decreases leukotriene synthesis. You can see that having higher levels of DGLA compared to AA which play an important factor for decreasing inflammation and increasing blood flow.

So how do you help your body block excess AA formation and tilt the balance back toward a favorable DGLA/AA ratio? By making sure your diet has adequate amounts of EPA. The importance of EPA is that it acts as a feedback inhibitor of the delta-5-desaturase enzyme. The higher the concentration of EPA in the diet, the more the delta-5-desaturase enzyme is inhibited, and the less AA is produced. As a result, the presence of EPA in the diet allows you to control the rate of AA production derived from DGLA, and thus generate a favorable DGLA to AA ratio in each cell membrane. This is why the AA/EPA ratio in the blood is such a powerful predictor of chronic disease.

Omega-3 Fatty Acids
The synthesis of long-chain Omega-3 fatty acids is much more complex as shown below.
Synthesis of Long-Chain Omega-3 Fatty Acids

Alpha Linolenic Acid (ALA) (C18:3)
Delta-6 desaturase
Steradonic Acid (C18:4)
Elongase
Eicosatretaenoic Acid (C20:4)
Delta 5-desaturase
Eicosapentaenoic Acid (EPA) (C20:5)
Elongase
C22:5
Elongase
C24:5
Delta-6 desaturase
C24:6
Perioxsomal degradation
Docosahexaenoic Acid (DHA) (C22:6)
Perioxsomal degradation
Eicosapentaenoic Acid (EPA) (C20:5)


The synthesis of EPA is seemingly relatively straight-forward from the short-chain Omega-3 fatty acid, alpha linolenic acid (ALA), just as the synthesis of arachidonic acid is from its short-chain precursor, linoleic acid. However, alpha linolenic acid is an inhibitor of the delta-6-desaturase enzyme, just as EPA is a feedback inhibitor of the delta-5-desaturase enzyme. This feedback inhibition makes the formation of EPA much more difficult that it should be. This is why studies comparing dietary intake of ALA versus EPA have indicated that the efficiency of making EPA from ALA is extremely limited. Therefore if you want get the greatest benefit of EPA, it will have to come from eating fish oil as opposed to vegetable sources rich in ALA (such as flaxseed).
Now it gets even more complex when going further on to make the DHA that is critical for the brain. The EPA must be elongated and then converted again by the delta-6-desaturase enzyme to the precursor of DHA which then must be shortened by perioxsomal enzymes into DHA. The result is that the synthesis of DHA from ALA is even more difficult than the synthesis of EPA (which isn't very good to begin with). Furthermore, DHA acts as a feedback inhibitor of the delta-6-desaturase enzyme that further reduces the flow of ALA to EPA and DHA. You can begin to see why until modern man starting eating shellfish some 150,000 years ago, that his ability to have adequate levels of long-chain Omega-3 fatty acids for his brain was highly compromised.

DHA can also be retro-converted into EPA by the same perioxosmal enzymes used necessary to make DHA in the first place, Although the process is not that efficient, but at least it provides a mechanism by which vegetarian sources (genetically modified algae) of DHA can provide EPA. This retroconversion process appears to be a more efficient way of making EPA for someone following a vegetarian diet than is its synthesis from ALA.

This is why long-chain Omega-3 fatty acids, like EPA, are so important in my dietary program. They inhibit the delta-5-desaturase enzyme thereby restricting the flow of any Omega-6 fatty acids into arachidonic acid, which therefore decreases the production of "bad" eicosanoids. As long as you are consuming very moderate amounts of Omega-6 fatty acids with equal amounts of EPA, then those dietary Omega-6 fatty acids in your diet tend to accumulate at the level of DGLA (because of the inhibition of delta-5-desaturase by the EPA), which increases the production of "good" eicosanoids. However, the total of amount of Omega-3 and Omega-6 fatty acid you need is relatively low. This means you still have to add some extra fat to your diet to help slow the rate of entry of carbohydrate to control insulin secretion. And the fat should be primarily monounsaturated fat. Monounsaturated fats can't be made into eicosanoids ("good" or "bad"). Thus by having no effect on eicosanoids nor insulin, monounsaturated fats can provide the necessary amount of fat for controlling the entry rate of carbohydrates into the bloodstream without disturbing the hormonal balances that you are trying to achieve through the OmegaRx Zone.

The Spillover Effect
In the early days, I thought that simply controlling the ratio of EPA and adding the right amount of GLA would be all that I needed to control eicosanoids. Taking all the data into account, including the increasingly massive over-consumption of Omega-6 fatty acids in general, I believed that a 4:1 ratio of EPA to GLA should do the trick. I thought one ratio would work for everyone. This was obviously flawed thinking in retrospect, but since I was coming from my background in pharmaceutical drug delivery, it seemed logical at the time. So I started out with this ratio, made some soft gelatin capsules containing both fish oil (the source of EPA) and borage oil (the source of GLA), and found some friends who were willing to be guinea pigs. I gave them my standard phrase, "Trust me".

Since I was only working with changing fatty acid levels during this early phase of my research, my initial observations on eicosanoids were not confounded by other potentially hormonally modulating approaches, like controlling insulin or restoring endocrine hormone levels. I had a very targeted approach to focus solely on manipulating eicosanoid levels through dietary supplementation with defined amounts of activated essential fatty acids. And many of the physiological changes I observed occurred within weeks, if not days.

The time frame for these physiological actions was important because it was much faster than the reported responses for treatments that focus on the restoration of endocrine hormones. Those changes usually take weeks, if not months, to see measurable effects.

After several months, however, I noticed that strange things seemed to be happening. Virtually everyone who took the combinations of EPA and GLA felt much better initially. After all, they were now making more "good" and fewer "bad" eicosanoids since I was changing the DGLA/AA balance in the cells. With time, some individuals mentioned that they seemed to have stabilized or that they even saw a drop-off in the early benefits they first experienced. Nonetheless, they still felt better than before they started. However, there was another smaller group, who saw their initial benefits erode completely and actually began to feel worse than when they started. Some of my friends were no longer quite so friendly, until I figured out what was happening. I called it the "spillover" effect.

Initially, as the ratio of DGLA to AA improves, the person begins making more "good" eicosanoids and fewer "bad" ones. Everything just keeps getting better. But there will be some point in time, depending on your biochemistry and gender, that the DGLA to AA ratio begins to degrade as more of the DGLA gets converted into AA. They still feel better than when they started, but not quite as good as they first did. For some individuals, this degradation of the DGLA/AA ratio continues to the point that they begin to feel worse than when they first started the program because they are now making many more "bad" eicosanoids. This is shown in the figure below.


These particular individuals developed a buildup of DGLA in their cells. The increased levels of DGLA were providing more substrate for the delta-5-desaturase enzyme to make more AA. The increase in DGLA was overwhelming the amount of EPA being supplied to inhibit the delta-5-desaturase enzyme. This spillover effect seemed to occur more often in females than in males. So much for the "one size fits all" ratio of GLA to EPA.

So I decided that if one size does not fit all, I had better start making a wide array of different EPA and GLA combinations and fine-tune them for each individual. But how could I do this? Fortunately eicosanoids do leave a biochemical audit trail that gives an insight into their actual balance in different organs in the body. That's what led me to develop the Eicosanoid Status Report to provide me with information on how to alter the amounts and ratios of activated essential fatty acids to fine-tune these exceptionally powerful hormones. (Now the AA/EPA test makes it even more precise.)
By 1989, I thought I had finally gotten this concept down to a science. A more complex science than I had originally thought, but one still governed by some basic biochemical rules. However what finally gave me the insight for the OmegaRx Zone was my work with elite athletes.

I began to notice that some of the elite athletes I was working with would have great training sessions, but then not do as well during competition. Others would do extremely well. When I started to ask them if they were doing anything different from a dietary standpoint prior to competition, it turned out that those who were carbohydrate-loading prior to a competition always appeared to do worse than those who maintained a consistent diet. I racked my brain trying to understand what had gone wrong or what had changed to explain this sudden shift in their eicosanoid status. Then it struck me. It was carbohydrate-loading that was increasing their insulin levels. This also explained the rapid decrease in the performance of the Stanford University swimmers who switched off my dietary recommendations and went back to eating dorm food composed primarily of high-density carbohydrates.
A trip to the bowels of the MIT library confirmed my suspicion. There I found previously published research that demonstrated that high levels of insulin activate the delta-5-desaturase enzyme, whereas glucagon inhibits this enzyme's activity. All the hormonal benefits I had carefully crafted for each athlete to manipulate their ratios of DGLA to AA were being undermined by the surge of insulin caused by their elevated carbohydrate intake. This increase in insulin stimulated the delta-5-desaturase enzyme to increase the production of AA at the expense of DGLA. For these athletes, the result was that a highly favorable DGLA to AA ratio created during training quickly became a very undesirable ratio at the time competition. It was the same spillover effect that I had observed in the early days of learning how to fine-tune eicosanoid levels. It was at that point I knew that I would never be able to control eicosanoid levels without controlling insulin first. It was back to the drawing board.
Was there any confirming evidence that high levels of insulin would affect the DGLA to AA ratio in humans? Fortunately, that information was published in 1991. The goal of that research was to maintain a high level of insulin for six hours in both normal subjects and patients with Type 2 diabetes (who are characterized by excessive insulin levels After only six hours of exposure to elevated insulin levels, the ratio of DGLA to AA in the bloodstream in both healthy individuals and Type 2 diabetics had dropped by nearly 50 percent. The elite athletes who were carbo-loading prior to competition were suffering the same decrease in DGLA/AA ratios by eating more high-density carbohydrates (grains, pasta, and starches), thus increasing insulin, which caused a rapid deterioration of their DGLA/AA ratios.

So now the metabolism of activated essential fatty acids had to be modified to take into account the role of insulin and glucagon on the delta-5-desaturase enzyme. This is shown below.

Effect of Elevated Insulin on the Metabolism of Activated Essential Fatty Acids

Dihomo Gamma Linolenic Acid (DGLA)

Delta-5 Desaturase
Activated by Insulin
Inhibited by EPA


Arachidonic Acid (AA)


Insulin was an activator of the delta-5-desaturase enzyme. The role of excess insulin in negatively affecting eicosanoid balance also explained why excess insulin was highly associated with heart disease. It wasn't that insulin was a cause, but that it drove the metabolism of essential fatty acids to make more arachidonic acid, and therefore more "bad" eicosanoids. The more "bad" eicosanoids you make, the more likely you will promote platelet aggregation and increased vasoconstriction, the underlying factors for a heart attack.

I knew the only way to control insulin required controlling the protein-to-carbohydrate ratio at every meal. Again I was confronted by what the optimal ratio of protein-to-carbohydrate ratio should be? A good beginning was to attempt to estimate the ratio of protein-to-carbohydrate ratio consumed by neo-Paleolithic man some 10-40,000 years ago, since our genes haven't changed that much since then.

Fortunately, such an estimate did exist in research published in an 1985 issue of The New England Journal of Medicine. Using anthropological data and comparing a large number of existing hunter-gatherer tribes, these researchers estimated the average protein-to-carbohydrate ratio in neo-Paleolithic diets to be approximately 3 grams of protein for every 4 grams of carbohydrate, or a protein-to-carbohydrate ratio of 0.75. Using this research as a starting point, I began developing a diet that would control the protein-to-carbohydrate ratio in a range between 0.5 and 1.0 at every meal so that the balance of insulin and glucagon would be maintained from meal to meal. This is the foundation of the insulin control component of my dietary recommendations.
Thus, my dietary program controls both the ratio of long-chain Omega-3 fatty acids to Omega-6 fatty acids as well as the balance of protein-to-carbohydrate at every meal while restricting total calories. This dietary strategy maintains the dynamic balance of eicosanoids by controlling the levels of the actual precursors and the hormones responsible for activating the critical enzymes in essential fatty acid metabolism. By keeping the balance of eicosanoid precursors in an appropriate zone (after all, you need some "bad" eicosanoids to survive), you also control the information flow of your Biological Internet. Control that flow and avoid hormonal miscommunication, and you have begun to reverse the aging process.

The development of chronic diseases (heart disease, diabetes, cancer, and arthritis) associated with aging does not occur overnight but is the result of constant hormonal insults to your body. But by the time they do appear, significant (and potentially irreversible) organ damage may have occurred. So if eicosanoids act as master hormones that control this complex hormonal communication system, is there some way we can continue to monitor and fine-tune this ultimate mechanism of aging before chronic disease conditions appear? If so, then you could tell when you are moving out of the appropriate eicosanoid zone and then take immediate dietary steps to restore that balance? There are very few direct diagnostic tests for eicosanoids. However, the ratio of AA/EPA will provide a remarkably good insight into your eicosanoid status. More importantly, this is a blood parameter that can be changed rapidly within 30 days.

Now... questions?

more info - http://www.itmonline.org/arts/lox.htm