Markers of the Zone
Markers of the Zone
You can’t control what you can’t measure. The Resolution Response is controlled by hormonal and genetic factors that are exceptionally difficult to measure because they either don’t circulate in the blood (like NF-kB or AMP kinase) or because of an extremely short lifetime at vanishingly low levels (such as eicosanoids and resolvins). However, there are blood markers that are easily measured in the blood that indicate whether or not your Resolution Response is optimized. These blood markers define the Zone.
Being in the Zone indicates that you have done your best to optimize your Resolution Response. Since the markers of the Zone can be easily measured in the blood, this enables you to optimize your Resolution Response using the Zone Pro-Resolution Nutrition system with great precision.
Coming from a pharmacological and academic background, I know it is essential to have clinical markers to support your statements no matter how effectively any potential drug or dietary intervention may be working. Otherwise, you are simply fooling yourself.
My basic contention is that virtually all chronic diseases are the consequence of increased levels of chronic unresolved cellular inflammation leading to loss of function. The extent of that unresolved inflammation can be easily determined by the clinical markers that also define the Zone. Thus, your ability to maintain a robust Resolution Response to reduce unresolved cellular inflammation can also be used to define your current state of wellness and ultimately increasing your healthspan. This is why the markers of the Zone are also ultimately markers of your true extent of wellness.
Rules for Useful Clinical Markers
For a clinical marker to be useful, it must be validated. That means it must be reproducible from lab to lab. The more complex the marker (and that usually means the more expensive the equipment used to measure it), the less likely the probability it can be validated from one lab to another. In other words, any clinical result is relatively useless unless it can be replicated by someone else. This doesn’t mean someone is lying to you, but the complexity of the sample preparation and the sophistication of instrumentation often makes the interpretation of the results non-reproducible in the hands of someone else who is equally qualified to do the test.
Furthermore, any clinical test used to define the Zone should come from the blood. The blood doesn’t lie. In addition, the meaning of the test must be easily understood by yourself without a lot of hand waving by someone else. Finally, the results of the blood test should give you a clear direction of what dietary steps you have to undertake to optimize your Resolution Response.
Markers of the Zone
Over the years, I have developed three blood markers for the Zone that meet all of the above criteria. Each one looks at each of the different components (reduction, resolution, and repair) that constitute the Resolution Response. Furthermore, all three markers must be within their appropriate ranges needed to keep you in the Zone. Each marker measures a different aspect of the Resolution Response. If all three tests are not in their optimal ranges, then you are simply not in the Zone and can’t optimally heal the damage created by an injury. Finally, if you are not in the Zone, then you can’t be considered well. If you are not in the Zone, this means that unresolved cellular inflammation building up in your body will continue to block your Resolution Response. So, let’s look at each of the markers of the Zone in greater detail.
TG/HDL Ratio: Measuring your ability to reduce diet-induced inflammation
How well you reduce diet-induced inflammation is best measured by the TG/HDL ratio. This marker is a surrogate marker of insulin resistance, primarily in the liver but also in other insulin-sensitive organs (muscles, adipose tissue, and the brain).
The liver is the body’s central assembly plant where dietary fatty acids are transported from the gut and then metabolized into lipoproteins which are then sent back out into the blood to transport the fatty acids to the other organs. Insulin is the hormone that controls much of the metabolism that takes place in liver. One of the first consequences of diet-induced inflammation in the liver is the development of insulin resistance in that organ. This results in a dysfunctional processing of lipoproteins resulting in triglycerides (TG) levels rising and HDL cholesterol levels falling.
The TG/HDL ratio is easily calculated from results you get in most standard annual physicals, although you may have to do a little simple math to determine the TG/HDL ratio.
The following table shows the ranges of TG/HDL ratios and how they correspond to the level of diet-induced inflammation in the liver, and probably every other insulin-sensitive organ in the body.
TG/HDL ratio Degree of insulin resistance
Greater than 3 High
Less than 1 Ideal
You want your TG/HDL ratio to be less than one. The optimal dietary intervention to lower your TG/HDL ratio is to follow the Zone Diet. The Zone Diet will lower your TG/HDL ratio significantly within 30 days due to the rapid reduction of insulin resistance.
AA/EPA ratio: Measuring your ability to resolve cellular inflammation
The best indication of your ability to resolve residual cellular inflammation is the AA/EPA ratio. The AA/EPA ratio also correlates very well with the levels of various cytokines (inflammatory proteins produced by activation of NF-kB) in the blood. As you lower the AA/EPA ratio, the levels of the inflammatory cytokines are also lowered. Remember cytokines are the pro-inflammatory proteins released from your cells if unresolved cellular inflammation remains elevated.
Arachidonic acid (AA) is the molecular building block for eicosanoids and eicosapentaenoic acid (EPA) is the molecular building block for resolvins. The better their balance in your blood, the greater your ability to resolve residual cellular inflammation.
The first use of the AA/EPA ratio to demonstrate its correlation with the reduction of inflammatory cytokines appeared in the New England Journal of Medicine in 1989. Its use in clinical research has been extremely robust over the years demonstrating as you lower the AA/EPA ratio, there is a significant clinical improvement of various chronic disease conditions including cardiovascular, auto-immune diseases, and neurological diseases. Most importantly, recently published research demonstrates the lower your AA/EPA ratio, the longer you live.
The following table indicates the AA/EPA ratio ranges of you want to achieve to maintain your wellness.
AA/EPA ratio Risk of developing a future chronic disease
Greater than 15 High
Less than 1 Moderate
The higher the AA/EPA ratio, the lower your potential to resolve any existing residual cellular inflammation in your body. The ideal ratio is similar to that found in the Japanese population who have the greatest longevity, greatest healthspan (i.e. longevity minus years of disability), lowest rates of heart disease as well as the lowest rates of depression in the industrialized world. Can your AA/EPA ratio be too low? Possibly, because you might increase the risk of bleeding or not be able to initiate an adequate inflammatory response once the AA/EPA ratio drops below 1.
So how do various populations rank in their AA/EPA ratios? The Japanese are usually between 1.5 and 3. Italians are between 10-15, and Americans are 20 or greater. This marker indicates that Americans are one of the most inflamed populations in the world and goes a long way of explaining the rapidly growing cost of health care in America.
The best way to reduce the AA/EPA ratio is to supplement your diet with increased levels of omega-3 fatty acids while simultaneously reducing your intake of omega-6 fatty acids.
HbA1c: Measuring your ability to repair damaged tissue caused by unresolved cellular inflammation
A very good clinical marker that defines your ability to repair the tissue damaged by cellular inflammation is the level of glycosylated hemoglobin also known as HbA1c. Although this blood marker is usually used to confirm the presence of diabetes; it is also a good marker of oxidative stress. Oxidative stress is usually a consequence of the over-production of free radicals indicating that less energy is being produced by your cell to repair tissue damage. Also, the higher the HbA1c, the more you inhibit the activity of AMP kinase. This is why diabetics have lower AMP kinase activity than non-diabetics. AMP kinase must be operating at peak efficiency to complete the last critical step necessary to optimize the Resolution Response.
The following table of HbA1c levels estimates the levels of oxidative stress in your body.
HbA1c Degree of Oxidative Stress
Greater 6.5% Very High
5.7 to 6.4% High
5.2 to 5.6% Moderate
Less than 4.9% Moderate
The reason that having a HbA1c level of less than 4.9% is less than ideal is because this may indicate the body is increasing cortisol secretion to maintain blood glucose levels by a process known as neo-glucogenesis. This often happens when following ketogenic diets as discussed later in this book. It should be noted that increased cortisol generates insulin resistance (this makes you fat) as well as lowering your immune response (this makes you sick).
The best way to decrease oxidative stress is supplementation with high-dose polyphenol extracts. They not only activate genes that reduce oxidative stress, but also increase the efficiency of energy production needed to repair damaged tissue by their activation of AMP kinase. If your level of HbA1c is higher than the ideal range, then the fastest way to increase your ability to repair tissue damaged by cellular inflammation is to increase your intake of polyphenols.
Each of these three markers needs to be in their ideal range for you to be considered well because only then will your Resolution Response be optimized. In other words, you want to be in the Zone. If any of the three markers is outside their ideal range, you have the appropriate dietary intervention to bring each of these markers back into their appropriate target ranges. Consider these markers of the Zone as your navigational buoys of wellness.
Subjective markers of the Zone
People still hate to give blood, let alone pay for a blood test. Are there any subjective markers that might indicate you are moving toward the Zone? Actually, there are several.
The first is the lack of hunger or fatigue for four to five hours after a meal. This indicates you are controlling the hormones in the blood and the gut that generate satiety signals to the brain. As demonstrated by Harvard researchers in 1999, the hormonal changes induced by any meal are rapid, but will usually last no more than five hours. The goal of the Zone Diet is the generation of the appropriate hormonal changes to prevent hunger and mental fatigue for the next four to five hours. Think of how many meals you typically consume that provide that level of satiety? The lower that number, the more you should consider following the Zone Diet.
Another marker that you can do on your own is determining your body fat percentage. The accumulation of excess body fat is a potential reservoir for unresolved cellular inflammation to spread to other organs as I explained in my book, Toxic Fat. Subjectively, you can determine if you have excess body fat by simply standing stark naked and look at yourself in the mirror. You can be even more precise by measuring your level of body fat using some simple measurements requiring only a tape measure. At www.zonediet.com/resources/body-fat-calculator you can find such a free body fat calculator to determine your levels of body fat.
Whatever method you use, the more excess body fat you have, the more likely you are generating more unresolved cellular inflammation. Ideally, your percent body fat should be no greater than 15 percent (for males) or 25 percent (for females) according to the American Council of Exercise. If your percent body fat is greater than 25 percent for males or 32 percent for females, then you are considered obese. Population studies conducted from 1999 to 2003 suggested that 70 percent of Americans would be considered obese based on their percentage of body fat whereas only 31 percent would be considered obese using the standard measurement of BMI. As I will discuss later, losing excess body fat is difficult, but any reduction of excess body fat indicates you are moving closer to the Zone.
Measuring appetite suppression with a watch or determining your percent body fat may sound a little simplistic. However, there are more precise subjective markers to indicate your progress toward reaching the Zone thus optimizing your Resolution Response.
Daily Performance: Increases in daily physical performance (especially increased energy) is indicative that you are producing more energy (in the form of ATP) with fewer calories. This will be reflected in both physical and mental performance as you stabilize blood sugar levels and reduce cellular inflammation in your fat cells, making it easier to release stored body fat for energy production. This is also an indication that AMP kinase activity is increasing.
Reduction in Desire for Carbohydrates: Your craving for carbohydrates will significantly decrease, if not be eliminated, as you stabilize blood sugar levels. If blood sugar levels are stable, then the brain has adequate levels of its optimal fuel to maintain peak energy production and thus maintain mental acuity. If blood sugar levels are too low (i.e. hypoglycemia), then you will have a constant desire for more dietary carbohydrates to help raise blood sugar levels for the brain’s energy needs.
Sleep: The need for sleep is determined by the amount of time required to re-establish neurotransmitter equilibrium. This process speeds up as you reduce inflammation in the brain.
Less grogginess upon waking: Grogginess upon waking is indicative of disturbances in your circadian rhythms that start the release of hormones to bring you out of deep sleep early in the morning. In other words, you won’t need that cup of caffeinated coffee in the morning to get you out of your morning stupor.
Sense of well-being: Another consequence of reducing neuro-inflammation is an improved state of constant well-being as opposed to being depressed, anxious, or constantly irritable.
Mental concentration: This is controlled by stabilizing blood sugar levels. One of the first signs of reduced insulin resistance is increased mental concentration with greater focus.
Reduction of headaches: Improving blood flow will reduce vasoconstriction, which is the underlying cause of most headaches. With adequate oxygen transfer to the brain, headache pain is reduced. An added benefit of getting more oxygen to the brain is to enhance your ability to think more clearly since you are producing higher levels of ATP.
Fingernail strength: The structural protein keratin is under strong dietary control. The Zone Pro-Resolution Nutrition system leads to rapid fingernail growth with improved strength.
Hair strength: Keratin is also the principal structural component of the hair. Hair texture and thickness of the hair fiber itself can be used as an indicator similar to fingernail strength.
Wrinkles and skin color: Reduction of cellular inflammation in the skin will also reduce degradation of collagen and elastin that causes the skin to form wrinkles. In addition, you will see better blood flow in the skin caused by the increased vasodilation of blood vessels located in the dermis thus improving facial color in the skin. As you move closer to the Zone, you will notice that wrinkles are decreasing in magnitude due to the accelerated rebuilding of collagen and elastin structure in the skin that comes with an improved Resolution Response.
Stool quality: The Zone Pro-Resolution Nutrition system will also improve gut nutrition with a corresponding increase in mucus production improving the speed at which food moves through your gut. The result is better stool quality and greater ease of exit from the colon.
Flatulence: Flatulence or gas is caused by the metabolism of anaerobic bacteria in the lower part of the intestine. This is your indication that adequate levels of fermentable fiber are reaching the bacteria in the colon. Better stool quality and increased movement of the stool through the colon, will significantly reduce bloating which is usually caused by a build-up of fermentation gases that can’t easily escape because of poor stool quality.
The physiological changes generated as you get closer to the Zone by using the Zone Pro-Resolution Nutrition system can be rapid. Some of these changes occur within hours, others within days, and most within a month. These benefits can easily be quantified in the blood and confirmed by a wide variety of subjective markers. However, as quickly as positive changes can be observed or measured, those same benefits can rapidly disappear because the hormonal and genetic changes induced by the Zone Pro-Resolution Nutrition system are short-term. That’s why following the Zone Pro-Resolution Nutrition system is a lifetime dietary program designed to keep your Resolution Response working at optimal efficiency.