The Resolution Response Theory of Chronic Disease
At the molecular level, all chronic diseases are initially driven by low-level unresolved cellular inflammation which is below the perception of pain. Such inflammation is a consequence of the blockage of the body’s natural healing response to the inflammation induced by any injury (1).  The scientific term that describes the molecular biology for this natural healing mechanism and how it is under profound dietary control is the Resolution Response™. 

New insights into the molecular biology of the Resolution Response has led to the development of a comprehensive nutritional program, the Pro-Resolution Nutrition system, that is personalized to maximize the individual’s healthspan defined as longevity minus years of disability. In other words, the Pro-Resolution Nutrition is a defined, personalized dietary pathway to simultaneously achieve improved treatment of existing chronic conditions as well as extending one’s healthspan. 

Such personalization is possible since each molecular component of the Resolution Response can be precisely modulated using the specific dietary components of the Pro-Resolution Nutrition system based on routine blood markers.

Resolution Response Theory of Chronic Disease
The history behind the concept of the Resolution Response theory of chronic disease started nearly 140 years ago with the development of Louis Pasteur’s germ theory (2,3).  While the germ theory was excellent for describing how bacteria and viruses cause infectious disease, it has not proved useful for understanding the causes of chronic diseases. 

Chronic disease is different than infectious disease. Chronic diseases are considered to be idiopathic conditions. This means they are of unknown origin unlike infectious diseases. I have been developing the Resolution Response theory of chronic disease over the past 35 years and it continues to evolve with new breakthroughs in molecular biology. It began with the awarding of the 1982 Nobel Prize in medicine to Sune Bergstrom, Bengt Samuelsson and John Vane for understanding the role of a group of pro-inflammatory hormones known as eicosanoids as major players in the initiation of inflammation (4). I realized this new appreciation of the role of eicosanoids had the potential to significantly alter medicine since the levels of eicosanoids are ultimately determined by the diet.  

My continued research into the role of diet and inflammation has expanded from this starting point to understand it is not inflammation per se that is the cause of chronic disease, but the blockage of the body’s internal healing response to tissue damage caused by chronic unresolved inflammation that is the underlying driving force for the development of a chronic disease.  Just like eicosanoids, the body’s internal Resolution Response is also ultimately controlled by the diet. 

Understanding Inflammation and Resolution
Inflammation can be best understood as a double-edged sword. There is a need for enough inflammation to combat microbial invasions and address physical injuries to keep us alive. However, unless that inflammation is resolved, the damage to the tissue caused by the initial injury will not completely heal. In other words, you need some inflammation to survive, but you have to reduce, resolve, and repair the damage caused by the initial inflammation to remain well and thus significantly delay the development of chronic disease. Furthermore, inflammation and resolution are separate active pathways of an overall balanced inflammatory response (5).

This constant balancing act between the molecular pathways that control inflammation and resolution and repair can best be summarized from the following figure in the form of a biological gyroscope. 

The duration of one’s healthspan is dependent on this constant balancing of inflammation and resolution.

The gene transcription factor NF-κB is the genetic master switch for turning on inflammation (6,7). This is because NF-κB controls the generation of inflammatory proteins known as cytokines as well as increasing the levels of the COX-2 enzyme that produces many of the pro-inflammatory eicosanoids. Eicosanoids are the hormonal agents that promote the intensity of inflammation. Together, cytokines and eicosanoids drive inflammation. On the other hand, resolvins are the hormones that turn off (i.e., resolve) inflammation (8).  In addition, resolvins enhance the body’s ability to kill and clear both bacterial and viral infections (9-11).

Finally, the gene transcription factor AMPK promotes the repair of the damage caused by the initial inflammation as well as inhibiting NF-κB (12).  As long as these gene transcription factors and hormones are in constant balance, the individual can maintain a zone of inflammation. This allows the individual to maintain an optimal healing response from any injury. The list of injuries that can cause an initial inflammatory response is quite extensive, as shown below: 

• Physical injuries (internal and external)
• Microbial invasions
• Diet-induced
• Oxidative stress-induced
• Surgery-induced
• Drug-induced (cancer drugs in particular)
• Stressor-induced (physical, emotional, and environmental)

The Resolution Response Theory of Chronic Disease provides a new molecular definition of wellness that can be defined as keeping inflammation in a therapeutic zone. That means generating an appropriate level of the initial inflammatory response to an injury to curtail the potential damage caused by that injury, but then balanced by an equal ability to resolve the injury induced-inflammation and repair the tissue damage caused by the initial inflammation.

How Chronic Disease Develops
Unlike infectious diseases, chronic diseases take years, if not decades, to develop. This is because they are often the consequence of long-term accumulated organ damage caused by a blocked Resolution Response exaggerated by constant diet-induced injuries.  Furthermore, the initial injury that caused tissue damage may have left the body many years earlier, but the incomplete healing of that initial inflammatory damage caused by a constantly blocked Resolution Response continues to build until there is enough accumulated organ damage to be termed as  a chronic disease. Now the individual requires the long-term use of medication to treat the symptoms of that particular chronic disease (as well as other co-morbidities) that started years, if not decades, earlier with a blocked Resolution Response.

Consequences of a Blocked Resolution Response
The first consequence of a blocked Resolution Response is the build-up of unresolved chronic inflammation by increasing the levels of pro-inflammatory mediators such as cytokines and eicosanoids. These inflammatory mediators can disrupt hormonal signaling patterns as well as reduce the efficiency of both the innate and adaptive immune systems (13,14). This disruption of the immune system is the first step leading to the generation of more insidious aspects of a blocked Resolution Response. These include development of senescent cells and acceleration of fibrosis, coupled with a compromised immune system with a reduced ability to remove senescent cells and fibrotic tissue from the body due to the presence of high levels of unresolved inflammation (15, 16). How unresolved inflammation leads to development of chronic disease at an earlier age is illustrated below. 

Cellular Senescence
One consequence of a blocked Resolution Response is the generation of senescent cells. Cellular senescence is a natural biological mechanism in which a cell permanently halts its division due to stressors on its genes (17).  Such senescent cells remain metabolically active but become incapable of further growth. Cellular senescence is the primary internal process the body utilizes to prevent tumor growth. However, cellular senescence can be induced by a diverse number of other external stressors causing DNA damage including drug-induced (especially cancer drugs), radiation, oxidative stress, mitochondrial dysfunction, and elevated glucose levels caused by insulin resistance. Whatever the cause, once a cell becomes senescent, it begins secreting large quantities of inflammatory mediators (including cytokines generated by NF-κB) that disrupt the local microenvironment of the tissue (18). This collection of inflammatory mediators is termed the Senescence Associated Secretory Phenotype or SASP. With a fully functional immune response, these inflammatory signals would normally act as beacons calling for the elimination of the senescence cells. However, excess unresolved cellular inflammation can overwhelm the immune system so that it doesn’t recognize these signals as effectively (19). The result is the senescent cells are not eliminated, and now become a permanent new source of continuous inflammation within the tissue. In addition to its adverse effects on tissue function, the SASP also contains factors that can induce the development of senescence in neighboring cells (20). This growing population of senescent cells sets off a cascade of inflammatory events that culminates in the generation of an increasingly dysfunctional organ that underlies the development of virtually all types of chronic diseases. It is becoming recognized that chronic diseases associated with aging (heart disease, diabetes, cancer, auto-immune, ocular,  Alzheimer’s, etc.) are strongly associated with increased levels of senescent cells in the body (21). 

Fibrosis
Just as cellular senescence is essential for stopping cancer development, it is also how wounds initially repair themselves.  However, if the immune system does not eliminate the senescent cells initially formed during the first steps of the wound repair process, then any further healing of the damaged tissue becomes compromised, SASP develops in the wound and scar tissue begins to develop in that area (22). With time, the organ function becomes compromised.  Examples of diseases characterized by fibrosis include the atherosclerotic lesions of heart disease, COPD, liver and kidney failure, neurological lesions such as Alzheimer’s, development of diabetes by loss of beta-cell function, and even obesity (as scar tissue can also form in the adipose tissue). More than 45 percent of all mortality is associated with significant fibrosis (23).

A primary cause of the inability of the immune system to remove senescence cells is chronic unresolved cellular inflammation (24). This ongoing inflammation creates molecular background noise that disrupts the intricate recognition system of the immune system to eliminate senescent cells leading to acceleration of chronic disease. Furthermore, the excess unresolved inflammation also makes it difficult for internal stem cells to replace the damaged cells to maintain normal organ function (25).

Dietary Control of the Resolution Response
What makes the Resolution Response so revolutionary is that it is under significant dietary control that can either optimize or inhibit its ability to control healing. This is because each dietary component of the Resolution Response interacts with the highly conserved genetic and hormonal mechanisms that compromise the Resolution Response. Therefore, the diet becomes the initial starting point for increasing one’s healthspan in the following ways: 

1. Reducing Inflammation by inhibiting NF-kB and decreasing eicosanoids

The Zone diet was developed as a highly defined and clinically validated, calorie-restricted diet that is protein-adequate, moderate in carbohydrate, and low in fat in order to modulate the hormonal responses generated by the diet to reduce inflammation by reducing insulin resistance (26). Hence, the Zone diet can be considered an anti-inflammatory diet (27). The hormonal responses induced by the Zone diet are short-lived (4-5 hours), so the hormonal orchestration generated by the Zone diet requires consistent application of dietary awareness (28). 

1. Increasing resolution and repair by increasing resolvins and activation of AMPK

Reducing inflammation with the Zone diet is only the first step toward completion of healing. Any reduced inflammation still has to be resolved by resolvins derived from high-dose omega-3 fatty acids, followed by the repair of damaged tissue mediated by activation of AMPK using high-dose polyphenols.

Consuming therapeutic levels of omega-3 fatty acids and polyphenols though a standard diet is a difficult process due to their naturally low concentrations requiring the consumption of often unrealistic amounts of fatty fish, fruits and vegetables and with the potential toxin contamination (heavy metals or polychlorinated biphenyls or PCBs) in traditional sources of these nutrients. This is why there is a need for highly refined and purified concentrates of omega-3 fatty acids and polyphenol extracts to achieve the needed concentrations to generate adequate levels of resolvins as well as to activate AMPK to complete the Resolution Response.

Polyphenols are compounds that give fruits and vegetables their color and are strongly associated with slowing the development of chronic disease as well as  decreased frailty and mortality and improved cognitive function (29-32). Activation of AMPK by polyphenols also inhibits the activity of NF-kB thus closing the loop of the Resolution Response to return the body back to homeostasis (12). The common term to describe this complex process is called healing.

Finally, there is considerable cross-talk between all three of these dietary components necessary for optimization of the Resolution Response. Thus, there must be a continuous orchestration and balance of each of these three unique dietary components to maintain an optimal Resolution Response to rapidly respond to random injury-induced inflammation.  

Going from Bench to Bedside
The Resolution Response is a highly orchestrated hormonal and genetic (mediated by gene transcription factors) process that is under profound dietary control. When optimized, the Resolution Response can neutralize, if not eliminate, the cellular inflammation induced by senescent cells regardless of its initial cause. Ideally, an optimal Resolution Response allows the immune system to eliminate senescent cells without toxicity since it is diet-based. This approach is known as senolysis as this stops the production of the SASP at its source. I believe such senolytic mechanisms generated by following the Pro-Resolution Nutrition program can have a superior benefit on reducing the potential progression of any age-related chronic disease. The result would be the slowing, halting, or even reversing particular chronic diseases associated with aging. However, this non-pharmaceutical approach requires a consistent and comprehensive nutritional intervention program that is personalized to the individual as determined by highly validated clinical parameters requiring only simple finger stick blood tests.

The core nutritional approach is to optimize the Resolution Response by reducing, resolving, and repairing the tissue damage caused by unresolved cellular inflammation. Published clinical data suggests the potential for this dietary technology is effective in addressing many chronic problems characterized by significant unresolved cellular inflammation including severe brain trauma (33), age-related macular degeneration (34), and the regeneration of beta-cell function in type 1 diabetes (35-38). All of these conditions can be linked to unresolved cellular inflammation, ultimately caused by a blocked Resolution Response.

 Defining Personalized Pro-Resolution Nutrition by Testing, Not Guessing
You can’t manage what you can’t measure. Medicine is no different.  The key to the Pro-Resolution Nutrition program is its personalization, which is also considered personalized medicine because of its impact on the optimization of the Resolution Response. 

The three markers used to optimize the Resolution Response are the following (1):

1. Triglyceride/HDL cholesterol (TG/HDL) ratio:  This is a surrogate marker of insulin   resistance. This marker can be significantly reduced by following the Zone diet.
2. Arachidonic acid (AA) to eicosapentaenoic acid (EPA) ratio: This is a marker of the balance of unresolved inflammation.  This marker is primarily reduced by high-dose omega-3 fatty acids.
3. Glycosylated hemoglobin (HbA1c): This is marker of long-term blood glucose control which will indicate the degree of inhibition of AMPK, as elevated blood glucose levels inhibit AMPK activity.  This marker is primarily reduced by high-dose polyphenols. 

These tests are convenient and inexpensive because they are finger stick tests and they can be done by the individual, a walk-in pharmacy, or in their physician’s office. They are recommended every three months in the first year of the program, and then on a yearly basis thereafter to ensure continuing movement toward optimizing one’s internal Resolution Response.

The ranges of these simple tests that indicate whether or not you have optimized your internal Resolution Response are the following:

Marker	Measures	Ideal Range
TG/HDL ratio	Insulin resistance	Less than 1
AA/EPA ratio	Balance of inflammation to resolution	1.5-3
HbA1c	Activation of AMPK	4.9-5.1%

Only when each of these markers are in their appropriate ideal ranges can you be considered to be well, meaning you have optimized your internal Resolution Response. 

It is estimated that less than one per cent of the American population currently have blood markers that consistent with the optimization of the Resolution Response. However, following the Pro-Resolution Nutrition program can make it possible within a matter of a few months. The key is to maintain those markers in their appropriate ranges as long as possible.

 Summary
A primary mission of modern medicine is to extend human healthspan by optimization of the body’s internal healing response. Aging is by far the greatest risk factor in predicting the development of chronic diseases such diabetes, heart disease, auto-immune, and neurological diseases. The Pro-Resolution Nutrition program can have an immediate impact in each of these broad chronic disease categories by optimizing the body’s internal Resolution Response. 

The data is becoming clearer that unresolved cellular inflammation caused by a blocked Resolution Response is a major factor in both the creation of both senescent cells and fibrosis. Furthermore, that same blocked Resolution Response is a major cause of the decreasing efficiency of the immune system (i.e., immunosenescence) that prevents the normal removal of senescent cells that leads to their persistence causing acceleration of chronic disease and continued organ fibrosis.

Understanding the Resolution Response and its profound dietary control ushers in new chapter in medicine. Rather than trying to manage the symptoms of chronic disease with drugs, a far greater emphasis should be placed on the ability of the diet to modulate the internal Resolution Response to maintain wellness as determined by the markers of the Zone as long as possible with the end goal of an increased healthspan (38).

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