Aspirin destroys Good Prostaglandins which protect stomach from dissolving

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Aspirin destroys " Good Prostaglandins " which protect the stomach

from " dissolving itself "

 

Long-chain Essential Fatty Acids

 

 

 

Certain drugs inhibit the cyclo-oxygenase pathway of this eicosanoid

formation.

 

The most well known is aspirin which literally destroys a cyclo-

oxygenase enzyme on a one-on-one basis.

 

This is what is known as a suicide inhibitor. When you are suffering

from a headache or arthritic pain, you are overproducing " bad "

eicosanoids, but in particular " bad " prostaglandins.

 

The aspirin temporally shuts down all prostaglandin formation (but

not leukotriene formation),

until the cell can make more of the cyclo-oxygenase enzyme to

replace the ones destroyed by the aspirin.

 

However, you can't be using these suicidal soldiers forever,

 

as aspirin also

 

shuts down the synthesis of " good " prostaglandins,

 

especially those that protect the stomach from

" dissolving itself " .

 

When that happens, you get internal bleeding.

 

This is why there are more than 10,000 deaths per year associated

with the over-use of aspirin.

 

Other drugs known as non-steroidal anti-inflammatory drugs (NSAID's)

also inhibit the cyclo-oxygenase enzyme but not the lipo-oxygenase

enzyme that makes leukotrienes.

The common names for these NSAID's are Motrin, Advil, Aleve, and

others. Continued use of these NSAID's generates the same problems

as does long-term aspirin use.

 

COX Enzymes

 

The most common types of anti-inflammatory drugs are those that can

only affect those eicosanoids that are synthesized via the cyclo-

oxygenase enzyme or COX. It was recently discovered there are two

forms of this enzyme known as COX-1 and COX-2.

COX-1 enzymes are a constant fixture of the vascular cells that line

the bloodstream or in stomach cells that secrete bicarbonate to

neutralize stomach acid.

 

COX-2 appears to be an enzyme that is synthesized only in response

to inflammation.

Standard drugs like aspirin and NSAID's (like Advil) don't

discriminate between these specific forms of the COX enzyme, which

is why they have side-effects associated with their long-term use.

 

For example, it appears that the anti-cancer benefits of aspirin may

stem from its inhibition of COX-2, whereas the side-effects (like an

increased risk of internal bleeding) come from its simultaneous

inhibition of COX-1.

 

However, this same inhibition of the COX-1 enzyme appears to convey

the cardiovascular benefits associated with aspirin. This may

explain why long-term use of COX-2 inhibitors may not work to

decrease heart attack rates: They don't target the COX-1 enzyme.

 

Weighing the risks against the benefits presents a dilemma

associated with all drugs that affect eicosanoid synthesis.

 

LOX Enzymes

 

Unlike inhibitors of the COX enzymes, there are very few inhibitors

of the LOX enzymes. Since leukotrienes (particular LTB4) represent a

primary mediator of pain, then the only way to affect their

production is to use corticosteroids with all of their associated

side effects.

 

However, the leukotrienes synthesized from EPA are physiologically

neuter compared to those derived from arachidonic acid.

 

This is why the AA/EPA ratio is a very good indicator of the body's

potential to prevent the over-production of leukotrienes without

using resorting to the use of corticosteroids.

 

Drug companies are racing to develop new patentable drugs--ones that

affect the downstream enzymes that control eicosanoid production

from arachidonic acid. Overlooked in this frenzy by the drug

companies seeking new and more expensive drugs to go downstream to

modify eicosanoid synthesis, is that there is an existing " drug "

that can achieve all of these benefits without any side effects.

 

This is because it goes upstream to modify eicosanoid production by

reducing arachidonic acid levels.

 

That " drug " is high-dose fish oil since the elevated levels of EPA

will reduce the production of " bad " eicosanoids (such as PGE2 and

LTB4) derived from arachidonic acid.

 

 

Understanding Eicosanoids

Strange, mysterious, and almost mystical, eicosanoids are the key to

our health because they control the flow of information in our

Biological Internet (see Appendix C). Why are eicosanoids so

important? They were the first hormones developed by living

organisms more than 550 million

years ago. As such they can be considered " super-hormones " because

they

control the hormonal actions of other hormones. Furthermore, you

don't

have an eicosanoid gland since every one of your 60 trillion cells

can

make eicosanoids.

 

Even though they are earliest hormones (dating from 550 million

years

ago), eicosanoids only were identified in the 20th century starting

with

the discovery of essential fatty acids in 1929. It was found that if

fat

in the diet was totally removed, rats would soon die. Adding back

certain essential fats (then called Vitamin F) was found to enable

fat-deprived rats to live. Eventually as technologies advanced,

researchers realized that essential fats were composed of both Omega-

6

and Omega-3 fatty acids that both needed to be obtained in the diet

because the body could not synthesize them. The word eicosanoids is

derived from the Greek word for 20 which is eicosa, since all of

these

hormones are synthesized from essential fatty acids that are 20

carbon

atoms in length.

 

The first actual eicosanoids were discovered in 1935 by Ulf von

Euler.

These first eicosanoids were isolated from the prostate gland (an

exceptionally rich source of eicosanoids), and were called

prostaglandins (a small subset of the much larger family of

eicosanoids). Since it was thought at that time that all hormones

had to

originate from a discrete gland, it made perfect sense to name this

new

hormone a prostaglandin. With time it became clear that every living

cell in the body could make eicosanoids, and that there was no

discrete

organ or gland that was the center of eicosanoid synthesis.

 

To date biochemists have identified more than 100 eicosanoids and

are

finding more each year. The breakthrough in eicosanoids research

occurred in 1971 when John Vane finally discovered how aspirin (the

wonder drug of the 20th century) actually worked: It changed the

levels

of eicosanoids. The 1982 Nobel Prize in Medicine was awarded to Vane

and

his colleagues Bengt Samuelsson and Sune Bergelson for their

discovery

of how eicosanoids play a role in human disease.

 

My Journey into Eicosanoid Research

 

This is where my journey with eicosanoids first started twenty years

ago. It was apparent to me that if certain " bad " eicosanoids were

associated with chronic disease conditions (like heart disease,

cancer,

arthritis, and so on), then the key to wellness would be to induce

the

body to make more " good " eicosanoids and fewer " bad " eicosanoids.

Rather

than using drugs to achieve that goal, I reasoned I could use food

as if

it were a drug. All I needed to do was figure out the right balance

of

protein, carbohydrate, and fat that would turn food into this

beneficial

drug. After more than 20 years, I think I've come pretty close to

that

" drug " with the OmegaRx Zone.

 

Of course, my colleagues in academic medicine didn't quite share my

initial enthusiasm. Almost overnight, I went from being a respected

research scientist with numerous patents in the area of intravenous

drug

delivery systems for cancer drugs, to being called a snake-oil

salesman

because of my constant refrain that the appropriate diet could

change

the balance of eicosanoids throughout the body. Part of the problem

was

that very few of them even knew what an eicosanoid was.

 

I believe that the foundation of 21st century medicine will be the

manipulation of eicosanoids. Yet ask most physicians and medical

researchers what an eicosanoid is, and you will usually get a blank

stare. I guess they're not familiar with the Nobel Prize winning

research. As unknown as they are to the medical community,

eicosanoids

are the hormones that maintain the information fidelity of your

Biological Internet, which means they become the key to health and

longevity.

 

Why are eicosanoids so unknown if they are so important? First, they

are

made, act, and self-destruct within seconds making them very

difficult

to study. Second, they don't circulate in the blood stream making it

extremely difficult to sample them. Finally, they work at

vanishingly

low concentrations making it almost impossible to detect them.

Despite

these barriers, more than 87,000 articles on eicosanoids have been

published in peer-reviewed journals. So, the basic research

community is

interested in eicosanoids even if your doctor never learned about

them

in medical school.

 

Eicosanoids encompass a wide array of hormones, many of which

endocrinologists have never heard of. They are derived from a unique

group of polyunsaturated essential fatty acids containing 20 carbon

atoms. The different classes of eicosanoids are shown below

Subgroups of Eicosanoids

 

Prostaglandins

 

Thromboxanes

 

Leukotrienes

Lipoxins

Hydroxylated fatty acids

Aspirin-triggered Epi-lipoxins

Isoprostanoids

Epoxyeicosatrienoic acids

Endocannabinoids

 

Now if you mention the word prostaglandins to physicians, they are

likely to have heard of those particular hormones. However,

prostaglandins are only a small subgroup of the eicosanoid family.

Some

of the other subgroups have been discovered only recently. As an

example, aspirin-triggered epi-lipoxins are the ones that give rise

to

the powerful anti-inflammatory properties described in the chapter

on

heart disease were discovered only a few years ago.

 

The glory days of eicosanoid research lie ahead with new eicosanoids

continually being discovered and a growing realization of the vast

role

these hormones play in controlling other hormonal systems. This fact

has

not been lost upon pharmaceutical companies, which have already

spent

billions of dollars trying to develop eicosanoid-based drugs.

Eicosanoids as drugs, however, have a very limited role in the world

of

pharmaceuticals. They are not only too difficult to work with, but

they

are also too powerful to be used as a drug.

 

There does remains one way to directly manipulate eicosanoids: your

diet. The reason why your diet can be successful where the largest

drug

companies have been unsuccessful is based on evolution. Eicosanoids

were

the first hormonal control system that living organisms developed.

You

can't have organized life unless you have cell membranes separating

the

internal workings of the cell from its environment. Since all cell

membranes contain fatty acids (including the building blocks of

eicosanoids, which are known as essential fatty acids), the cell's

own

membrane became the ideal reservoir for eicosanoid synthesis since

you

could always be certain that the raw materials for making these

hormones

were close by.

 

As autocrine hormones, eicosanoids' mission is to be secreted by the

cell to test the external environment and then report back to the

cell

what was just outside by interacting with its receptor on the cell

surface. Based on that information, the cell could then make the

appropriate biological action (via the appropriate second messenger)

to

respond to any change in its environment.

 

In biotechnology, one of the hot research areas today is the field

of

biological response modifiers. Eicosanoids represent the first (and

probably the most powerful) biological response modifiers developed

by

living organisms. In fact, many of the eicosanoids that we make in

our

bodies today are identical to ones made by sponges beginning

hundreds of

millions of years ago.

 

The reason why eicosanoids play such a central role in our

physiology is

due to the second messengers that certain eicosanoids generate.

There

are a variety of eicosanoid receptors on the surface of the cell,

and

depending on which eicosanoid interacts with the receptor, a

specific

second messenger is then synthesized by the cell. Sometimes a second

messenger, such as cyclic AMP is generated, and sometimes a totally

different second messenger, such as the DAG and IP3 system, is

generated. If one second messenger goes up, then the other goes

down. In

essence, the complexity of your Biological Internet is reduced to a

digital system consisting of green and red lights.

 

Those eicosanoids that generate increased production of cyclic AMP

are

your key to maintaining wellness. Why? Cyclic AMP is the same second

messenger used by a number of endocrine hormones in the body to

translate their biological information to the appropriate target

cell.

By maintaining adequate cellular levels of those eicosanoids that

increase cyclic AMP levels, you are guaranteed that a certain

baseline

level of cyclic AMP is always present in a cell. Thus, it's far more

likely that the overall cyclic AMP level in the cell will be high

enough

to ensure that an appropriate biological response (i.e. better

hormonal

communications) is generated.

 

How can you tell a " good " eicosanoid from a " bad " eicosanoid?

 

An eicosanoid's effect on second messengers becomes the definition

of a

" good " or " bad " eicosanoid. A " good " eicosanoid will increase the

levels

of cyclic AMP in a cell, whereas a " bad " eicosanoid will decrease

the

levels of cyclic AMP through the elevation of the levels of the

IP3/DAG

second messengers. The table below shows a listing of the types of

" good " and " bad " eicosanoids and their receptors they interact with.

 

Receptors for " Good " and " Bad " Eicosanoids

 

Receptor Effect on cyclic AMP

 

" Good " Eicosanoids

 

PGE1 EP2, EP4 increase

PGI2 IP increase

PGD2 DP increase

 

" Bad " Eicosanoids

 

TXA2 TP decrease

PGE2 EP1, EP3 decrease

PGF2a FP decrease

LTB4 BLT decrease

LTC4, Cys-LTI decrease

LTD4, LTE4 Cys-LT2 decrease

 

Once an eicosanoid interacts with its unique receptor, a second

messenger is then synthesized inside in the target cell. If a " good "

eicosanoid interacts with the right receptor, then cyclic AMP is the

second messenger that is formed. On the other hand, if a " bad "

eicosanoid interacts with its receptor then cyclic AMP levels are

decreased. Adding further to this complexity is that some

eicosanoids

such as PGA and PGJ are cyclopentenone eicosanoids. These

eicosanoids

don't have cell receptors on the surface as they can directly enter

into

the cell where they can interact with the cell's nucleus to effect

cellular growth and differentiation. Since there is no discrete

eicosanoid " gland " , there is no central site that turns " on "

or " off "

eicosanoid action. Nature solved this problem by developing

different

types of eicosanoids that have diametrically opposed physiological

actions. It is the balance of these opposing actions of different

eicosanoids to remain an equilibrium of biological activity. These

differences in biological actions are the foundation for the

eicosanoid

" axis " .

 

This eicosanoid " axis " is composed of " good " eicosanoids on one side

and

" bad " eicosanoids on the other. In the absence of the evolutionary

development of more advanced hormonal systems (like corticosteroids)

to

control this eicosanoid activity, this balance of " good " and " bad "

eicosanoids was the best solution that could be done at the time.

Obviously, there is no such thing as an absolutely " good " eicosanoid

nor

an absolutely " bad " eicosanoid, anymore than there is a moral

attachment

to " good " and " bad " cholesterol.

 

Most chronic diseases are a consequence of an imbalance of " good "

and

" bad " eicosanoids. I have already discussed in this book the role of

eicosanoids in heart disease, cancer, diabetes, arthritis, and

depression among others. The 1982 Nobel Prize in Medicine provided

me an

insight into the molecular nature of chronic disease since it could

be

seen as an imbalance in eicosanoid levels. It became apparent to me

at

the same time that the appropriate balance of eicosanoids could be

used

to provide a molecular definition of wellness. In essence, the more

the

balance of eicosanoids is tilted toward " bad " eicosanoids, the more

likely you are to develop chronic disease. Conversely, the more the

balance is tilted toward " good " eicosanoids, the greater the chance

that

you'll achieve wellness and longevity. The AA/EPA ratio will

indicate

where you stand in terms of such a balance.

 

If you are skeptical about the statement that eicosanoids play such

a

fundamental role in a such number of diverse disease conditions,

then

ask any physician what happens when they give a high dose of

corticosteroids to a patient for more than 30 days. The answer will

be

physiological devastation, if not death. This occurs because

corticosteroids have only one mode of action, they knock out all

eicosanoid production -- " good " and " bad " by inhibiting the release

of

essential fatty acids from cell membrane. This chokes off all supply

of

precursors to make any type of eicosanoid. Without eicosanoids, you

can't survive.

 

How Eicosanoids are Synthesized

 

Since eicosanoids are produced in every cell-not one specific gland--

 

it's as you have 60 trillion separate eicosanoid glands capable of

making these exceptionally powerful hormones. Unlike the endocrine

hormones, which are under control of the hypothalamus, there is no

such

central control on eicosanoids. Rather than responding to some

master

signal, each cell responds to changes in its immediate environment.

The

first step in generating a cellular response is the actual release

of an

essential fatty acid from the phospholipids in the cell membrane.

The

enzyme responsible for the release of the essential fatty acid is

called

phospholipase A2.

 

Since there is no feedback loop to stop the production of

eicosanoids,

the only way to inhibit their release from the membrane is by the

production of corticosteroids (such as cortisol) from the adrenal

gland,

which causes the synthesis of a protein (lipocortin) that inhibits

the

action of phospholipase A2. By inhibiting this enzyme, which

releases

essential fatty acids from the cell membranes, you choke off the

supply

of a substrate required for all eicosanoid synthesis. Obviously, if

you

are overproducing corticosteroids (or taking corticosteroid drugs),

you

will bring all eicosanoid synthesis to a crashing halt, which can

cause

the shut down of your immune system.

 

The most powerful eicosanoid modulating drugs are corticosteroids.

As I

mentioned above, they inhibit the release any essential fatty acid

so

that no eicosanoids can be synthesized. Obviously, if you have

intense

pain or inflammation, this may be your only course of action on a

short-term basis. Over the long term, corticosteroid therapy lowers

the

response of your immune system, decreases cognitive function,

increases

fat stores, thins the skin, and accelerates osteoporosis. In fact,

if

you give a single injection of corticosteroids to healthy

individuals,

their lymphocytes will be very similar to those in AIDS patients

within

24 hours.

 

 

Enzymes that Make Eicosanoids

 

There are three primary pathways an essential fatty acid (composed

of a

string of 20 carbon atoms), once released from the cell membrane,

can

follow. The first is via the cyclo-oxygenase system (i.e. COX) that

make

prostaglandins and thromboxanes. In this pathway the highly

contorted

essential fatty acid is closed upon itself to form a prostanoid

ring.

The second is through the 5-lipo-oxygenase (5-LIPO) pathway that

makes

leukotrienes. There is a third pathway in which the 20-carbon

essential

fatty acid is simply modified via either the 12 or 15-lipoxygenase

(12

or 15-LIPO) enzymes as in the case of hydroxylated essential fatty

acids. It is via this third pathway that many of the newly

discovered

eicosanoids are made. These pathways are shown below.

 

 

 

Types of Eicosanoid Synthesizing Enzymes

 

Long-chain Essential Fatty Acids

 

COX 5-LOX 12 and 15 LOX

 

Prostaglandins Leukotrienes Lipoxins and

and Thromboxanes Hydroxylated Fatty Acids

 

 

 

 

Certain drugs can inhibit the cyclo-oxygenase pathway of this

eicosanoid

formation. The most well known is aspirin which literally destroys a

cyclo-oxygenase enzyme on a one-on-one basis. This is what is known

as a

suicide inhibitor. When you are suffering from a headache or

arthritic

pain, you are overproducing " bad " eicosanoids, but in

particular " bad "

prostaglandins. The aspirin temporally shuts down all prostaglandin

formation (but not leukotriene formation), until the cell can make

more

of the cyclo-oxygenase enzyme to replace the ones destroyed by the

aspirin. However, you can't be using these suicidal soldiers

forever, as

aspirin also shuts down the synthesis of " good " prostaglandins,

especially those that protect the stomach from dissolving itself.

When

that happens, you get internal bleeding. This is why there are more

than

10,000 deaths per year associated with the over-use of aspirin.

Other

drugs known as non-steroidal anti-inflammatory drugs (NSAID's) also

inhibit the cyclo-oxygenase enzyme but not the lipo-oxygenase enzyme

that makes leukotrienes. The common names for these NSAID's are

Motrin,

Advil, Aleve, and others. Continued use of these NSAID's generates

the

same problems as does long-term aspirin use.

 

COX Enzymes

 

The most common types of anti-inflammatory drugs are those that can

only

affect those eicosanoids that are synthesized via the cyclo-

oxygenase

enzyme or COX. It was recently discovered there are two forms of

this

enzyme known as COX-1 and COX-2. COX-1 enzymes are a constant

fixture of

the vascular cells that line the bloodstream or in stomach cells

that

secrete bicarbonate to neutralize stomach acid. COX-2 appears to be

an

enzyme that is synthesized only in response to inflammation.

Standard

drugs like aspirin and NSAID's (like Advil) don't discriminate

between

these specific forms of the COX enzyme, which is why they have

side-effects associated with their long-term use.

 

For example, it appears that the anti-cancer benefits of aspirin may

stem from its inhibition of COX-2, whereas the side-effects (like an

increased risk of internal bleeding) come from its simultaneous

inhibition of COX-1. However, this same inhibition of the COX-1

enzyme

appears to convey the cardiovascular benefits associated with

aspirin.

This may explain why long-term use of COX-2 inhibitors may not work

to

decrease heart attack rates: They don't target the COX-1 enzyme.

Weighing the risks against the benefits presents a dilemma

associated

with all drugs that affect eicosanoid synthesis.

 

LOX Enzymes

 

Unlike inhibitors of the COX enzymes, there are very few inhibitors

of

the LOX enzymes. Since leukotrienes (particular LTB4) represent a

primary mediator of pain, then the only way to affect their

production

is to use corticosteroids with all of their associated side effects.

However, the leukotrienes synthesized from EPA are physiologically

neuter compared to those derived from arachidonic acid. This is why

the

AA/EPA ratio is a very good indicator of the body's potential to

prevent

the over-production of leukotrienes without using resorting to the

use

of corticosteroids.

 

Drug companies are racing to develop new patentable drugs--ones that

affect the downstream enzymes that control eicosanoid production

from

arachidonic acid. Overlooked in this frenzy by the drug companies

seeking new and more expensive drugs to go downstream to modify

eicosanoid synthesis, is that there is an existing " drug " that can

achieve all of these benefits without any side effects. This is

because

it goes upstream to modify eicosanoid production by reducing

arachidonic

acid levels. That " drug " is high-dose fish oil since the elevated

levels

of EPA will reduce the production of " bad " eicosanoids (such as PGE2

and

LTB4) derived from arachidonic acid.

 

 

 

Synthesis of Essential Fatty Acids

 

To understand the importance of diet in controlling these

eicosanoids

and re-establishing an appropriate eicosanoid balance, we have to

understand how the actual precursors of eicosanoids are made. To

begin

with, all eicosanoids ultimately are produced from essential fatty

acids

that the body cannot make, and therefore must be part of the diet.

These

essential fatty acids are classified as either Omega-3 or Omega-6

depending upon the position of the double bonds within them.

However,

typical essential fatty acids are only 18 carbons in length and must

be

further elongated to 20-carbon fatty acids by the body before

eicosanoids can be made. Remember, all eicosanoids come from

essential

fatty acids that are 20 carbon atoms in length. It is just not the

number of carbon atoms that count, but also their configuration.

Eicosanoid precursors must have a certain spatial configuration with

at

least three conjugated double bonds in order to be converted into an

eicosanoid. How your diet controls the formation of dietary

essential

fatty acids into the actual 20-carbon atom precursors of eicosanoids

is

a complex story.

 

The discovery of essential fatty acids was first reported in 1929.

At

that time essential fatty acids were called Vitamin F. But Vitamin F

was

useless unless transformed into an eicosanoid. Thus began a

continuing

70-year journey to understand how your diet does three things:

controls

eicosanoid formation; alters eicosanoid balance in the body; and

determines how eicosanoids become a central players in your health.

 

The differences between the two classes of essential fatty acids,

Omega-6 and Omega-3, are based on the position of the double bonds

within the fatty acid molecule. This is important since it is the

positioning of these double bonds that dictates their three-

dimensional

structure in space that ultimately determines how they interact with

their appropriate receptors. Although the synthesis of essential

fatty

acids use the same enzymes, their metabolic pathways are quite

different. The metabolism of long-chain Omega-3 fatty acids are more

complex, so let's start with the simpler pathway to make Omega-6

fatty

acids.

 

Omega-6 Fatty Acids

 

There are two key steps in this process that determine the amount of

eicosanoid building blocks that will be made. These are known in

biochemistry as " rate-limiting steps " . The first rate-limiting step

is

controlled by the enzyme delta-6-desaturase. This enzyme inserts a

necessary third double bond in the essential fatty acid in just the

right position to begin bending inward and forms gamma linolenic

acid

(GLA) from linoleic acid as shown in the figure below.

 

 

 

Synthesis of Omega-6 essential fatty acids into eicosanoid precursors

 

Linoleic Acid (C18:2)

 

Delta-6 desaturase

 

Gamma Linolenic Acid (GLA) (C18:3)

 

 

 

Elongase

 

Dihomo Gamma Linolenic Acid (DGLA) (C20:3)

 

Delta 5-desaturase

 

Arachidonic Acid (AA) (C20:4)

 

" Good " Eicosanoids " Bad " Eicosanoids

 

 

 

(The number after the C tells how many carbon atoms the essential

fatty

acid contains, and the number after the colon tells how many double

bonds there are in the essential fatty acid)

 

I define an activated essential fatty acid as any essential fatty

acid

that has this new double bond inserted by the delta-6-desaturase

enzyme.

This is because this new double bond starts bending the essential

fatty

acid to get the appropriate spatial configuration required to make

an

eicosanoid. Once this new double bond has been inserted into a

short-chain essential fatty acid, then very small amounts of these

activated essential fatty acids can profoundly affect eicosanoid

balance

in your body.

 

However, there are many factors that can decrease the activity of

delta-6-desaturase enzyme. The most important factor is age itself.

There are two times in your life during which this enzyme is

relatively

inactive. The first is at birth. For the first six months of life,

the

activity of this key enzyme in the newborn is relatively low. But

this

is also the time at which maximum amounts of long-chain essential

fatty

acids are required by the child since the brain is growing at the

fastest possible rate, and these long-chain essential fatty acids

are

the key structural building blocks for the brain. Nature has

developed a

unique solution to this problem: mother's breast milk. Breast milk

is

very rich in GLA and other long-chain essential fatty acids such as

the

EPA and DHA. By supplying these activated essential fatty acids

through

the diet, this early inactivity of the delta-6-desaturase enzyme is

overcome.

 

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 by getting into the OmegaRx Zone.

 

http://www.drsears.com/understandingeicosanoids.page

 

JoAnn Guest

mrsjo-

www.geocities.com/mrsjoguest/Diets