Chronic inflammation contributes to many leading causes of death in the United States:

• heart disease
• cancer
• diabetes
• stroke
• Alzheimer’s disease
• kidney disease
• chronic lower respiratory disease

Fortunately, fish oil, sesame lignans, and other integrative interventions can counteract destructive chronic inflammation.

Causes of Chronic Inflammation

Several factors contribute to chronic inflammation:

• Mitochondrial dysfunction
• Advanced glycation end products due to elevated blood sugar levels
• Uric acid crystals
• Oxidized lipoproteins (such as low-density lipoprotein)

Risk Factors Associated with Chronic Inflammation

Several risk factors promote chronic inflammation:

• Increasing age
• Obesity
• High saturated fat intake
• High sugar intake

Testing for Chronic Inflammation

Blood tests that can detect chronic inflammation include:

• High sensitivity C-reactive protein (hs-CRP)
• fibrinogen
• tumor necrosis factor-alpha (TNF-α)
• interleukin-1 beta (IL-1β)
• interleukin-6 (IL-6)
• interleukin-8 (IL-8)

Conventional Medical Treatments

Drugs that can help address chronic inflammation include:

• Pentoxifylline
• Metformin

Dietary and Lifestyle Changes

Several dietary and lifestyle changes can help reduce chronic inflammation:

• Low-glycemic diet
• Reduced consumption of:
• total and saturated fat
• cholesterol
• Increased exercise

Integrative Interventions

• Fish Oil: A higher intake of omega-3 fatty acids is associated with lower levels of markers of TNF-α activity, CRP, and IL-6.
• Specialized Pro-Resolving Mediators (SPMs): SPMs derived from marine oils help support the body's efficient resolution of the inflammatory response.
• Curcumin: Curcumin, a constituent of turmeric, has been studied in over 7000 published scientific articles and is known to modulate several important pathways including the ones involved in inflammatory processes.
• Magnesium: In several large observational studies, greater magnesium intake was associated with lower hs-CRP, IL-6, and TNF-α activity.
• Tea polyphenols: Tea polyphenols have been shown to produce reductions in CRP in human clinical studies.
• DHEA: Supplementation was shown to significantly decrease TNF-α and IL-6 levels in elderly volunteers, as well as lower visceral fat mass and improve glucose tolerance.
• Sesame lignans: Supplementation reduced the levels of a pro-inflammatory vasoconstrictor by approximately 30%.

Of the 10 leading causes of mortality in the United States, chronic, low-level inflammation contributes to the pathogenesis of at least seven. These include heart disease, cancer, chronic lower respiratory disease, stroke, Alzheimer’s disease, diabetes, and nephritis.^1-9

Inflammation has classically been viewed as an acute (short-term) response to tissue injury that produces characteristic symptoms and usually resolves spontaneously. More contemporary revelations show chronic inflammation to be a major factor in the development of degenerative disease and loss of youthful functions.

Chronic inflammation can be triggered by cellular stress and dysfunction, such as that caused by excessive calorie consumption, elevated blood sugar levels, and oxidative stress. It is now clear that the destructive capacity of chronic inflammation is unprecedented among physiologic processes.¹⁰

The danger of chronic, low-level inflammation is that its silent nature belies its destructive power.

In fact, stress-induced inflammation, once triggered, can persist undetected for years, or even decades, propagating cell death throughout the body. Due to the fact that it contributes so greatly to deterioration associated with the aging process, this silent state of chronic inflammation has been coined “inflammaging.”

Chronic low-level inflammation may be threatening your health at this very moment, without you realizing it. In this protocol you will learn about low-cost blood tests that can assess the inflammatory state within your body. You will also discover novel approaches that combat chronic inflammation to help avoid age-related health decline.

The Acute Inflammatory Response

Inflammation, the adaptive immune response to tissue injury or infection, plays a central role in metabolism in a variety of organisms.¹¹

At its most basic level, an acute inflammatory response is triggered by 1) tissue injury (trauma, exposure to heat or chemicals); or 2) infection by viruses, bacteria, parasites, or fungi. The classic manifestation of acute inflammation is characterized by four cardinal signs: Redness and heat result from the increased blood flow to the site of injury. Swelling results from the accumulation of fluid at the injury site, a consequence of the increased blood flow. Finally, swelling can compress nerve endings near the injury, causing the characteristic pain associated with inflammation. Pain is also important to make the organism aware of the tissue damage. Additionally, inflammation in a joint usually results in a fifth sign (impairment of function), which has the effect of limiting movement and forcing rest of the injured joint to aid in healing.

A well-controlled acute inflammatory response has several protective roles:

• It prevents the spread of infectious agents and damage to nearby tissues;
• helps to remove damaged tissue and pathogens; and
• assists the body's repair processes

However, a third type of stimuli, cellular stress and malfunction, triggers chronic inflammation, which, rather than benefiting health, contributes to disease and age-related deterioration via numerous mechanisms.

Cellular Stress and Chronic, Low-Level Inflammation

Mitochondria—cellular organelles responsible for generating biochemical energy in the form of adenosine triphosphate (ATP)—are a fundamentally necessary component of life in higher organisms. In fact, in the case of sophisticated multicellular life forms, organismal viability depends upon optimal mitochondrial function. Paradoxically, mitochondrial processes can also bring about a tissue-destroying inflammatory mediator known as the inflammasome; this phenomenon is provoked by damaged and dysfunctional mitochondria.¹²

Mitochondrial dysfunction arises consequent of exposure to exogenous (eg, environmental toxins, tobacco smoke) and endogenous (eg, reactive oxygen species) stressors, and as a result of the aging process itself. For example, a byproduct of mitochondrial energy generation is the creation of free radical molecules. Free radicals can damage cellular structures and initiate a cascade of proinflammatory genetic signals that ultimately results in cell death (apoptosis), or worse, uncontrolled cell growth—the hallmark of cancer.

Aging is associated with declining mitochondrial efficiency and increased production of free radical molecules. Recent research identifies this age-associated aberration of mitochondrial function as a principle actuator of chronic inflammation.¹³ Specifically, mitochondrial dysfunction brings about inflammation as follows:

1. Accumulation of free radicals induces mitochondrial membrane permeability;
2. Molecular components normally contained within the mitochondria leak into the cytoplasm (intracellular fluid in which cellular organelles are suspended);
3. Cytoplasmic pattern recognition receptors (PRR's), which detect and initiate an immune response against intracellular pathogens, recognize the leaked mitochondrial molecules as potential threats;
4. Upon detection of the potential threat, PRR's form a complex called the inflammasome that activates the inflammatory cytokine interleukin-1β, which then recruits components of the immune system to destroy the “infected” cell.¹⁴

These four steps represent a simplified scheme of mitochondrial dysfunction leading to cellular destruction; however, intracellular free radicals are not the only inducers of inflammatory cell death.

Circulating sugars, primarily glucose and fructose, are culprits as well. When these “blood sugars” come in contact with proteins and lipids a damaging reaction occurs forming compounds called advanced glycation end products (AGEs). AGEs bind to the cell-surface receptor called receptor for advanced glycation end products, or RAGE. Upon activation, RAGE triggers the movement of the inflammatory mediator nuclear factor kappa-B (NF-κB) to the nucleus, where it activates numerous inflammatory genes.¹⁵ AGEs are primarily formed in vivo, and glycation is exacerbated by elevated blood sugar levels. However, dietary AGEs also contribute to inflammation; they are abundant in foods cooked at high temperatures, especially red meat.^16,17

Additional biochemical inducers of a chronic inflammatory response include:

• Uric acid (urate) crystals, which can be deposited in joints during gouty arthritis; elevated levels are a risk factor for kidney disease, hypertension, and metabolic syndrome^18,19;
• Oxidized lipoproteins (such as LDL), a significant contributor to atherosclerotic plaques²⁰; and
• Homocysteine, a non-protein-forming amino acid that is a marker and risk factor for cardiovascular disease, and may increase bone fracture risk.²¹

Together, these proinflammatory instigators promote a perpetual low-level chronic inflammatory state called para-inflammation.¹¹

Although it progresses silently, para-inflammation presents a major threat to the health and longevity of all aging humans. Chronic, low-level inflammation is associated with common diseases including cancer, type II diabetes, osteoporosis, cardiovascular diseases, and others. Thus, by targeting the myriad physiological variables that can inaugurate an inflammatory response, one can effectively temper chronic inflammation and reduce their risk for inflammatory diseases.

Following is a list of some of the most prominent markers of inflammation used in research and diagnosis. Some can be detected by blood tests (see “Diagnosis and Conventional Treatment of Chronic Inflammation”):

Tumor Necrosis Factor-alpha

Tumor necrosis factor-alpha (TNF-α) is an intercellular signaling protein called a cytokine, which can be released by multiple types of immune cells in response to cellular damage, stress, or infection. Originally identified as an anti-tumor compound produced by macrophages (immune cells),²² TNF-α is required for proper immune surveillance and function. Acting alone or with other inflammatory mediators, TNF-α slows the growth of many pathogens. It activates the bactericidal effects of neutrophils, and is required for the replication of several other immune cell types.²³ Excessive TNF-α, however, can lead to a chronic inflammatory state, can increase thrombosis (blood clotting) and decrease cardiac contractility, and may be implicated in tumor initiation and promotion.⁷

Nuclear Factor Kappa-B

Nuclear factor kappa-B (NF-κB) is important in the initiation of the inflammatory response. When cells are exposed to damage signals (such as TNF-α or oxidative stress), they activate NF-κB, which turns on the expression of over 400 genes involved in the inflammatory response.²³ These include other inflammatory cytokines, and pro-inflammatory enzymes including cyclooxygenase-2 (COX-2) and lipoxygenase. COX-2 is the enzyme responsible for synthesizing pro-inflammatory prostaglandins, and is the target of non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, aspirin) and COX-2 inhibitors (Celebrex).

Interleukins

Interleukins are cytokines that have many functions in the promotion and resolution of inflammation. Pro-inflammatory interleukins that have been the subject of most research include IL-1β, IL-6, and IL-8. IL-1β helps immune cells to move out of blood vessels and into damaged or dysfunctional tissues. IL-6 has both pro-inflammatory and anti-inflammatory roles, and coordinates the production of compounds required during the progression and resolution of acute inflammation. IL-8 is expressed by both immune and non-immune cells, and helps to attract neutrophils (immune cells that can destroy pathogens) to sites of injury.

C-reactive Protein

C-reactive protein (CRP) is an acute-phase protein, one of several proteins rapidly produced by the liver during an inflammatory response. Its primary goal in acute inflammation is to coat damaged cells to make them easier to recognize by other immune cells.²⁴ CRP elevation above basal levels is not diagnostic on its own, as it can raise in several cancers, rheumatologic, gastrointestinal, and cardiovascular conditions, and infections.²⁵ Elevation of CRP (as determined by a high-sensitivity CRP assay or hs-CRP) has a strong association with elevated risk of cardiovascular disease and stroke.²⁶

Eicosanoids

The cytokine factors mentioned earlier (interleukins, TNF-α) are “long-distance messages.” They are produced by cells at the site of inflammation and released into the blood, carrying information about the inflammatory response throughout the body. In contrast, eicosanoids are “local” messages; they are produced by cells that are proximal to the site of inflammation, and are meant to travel short distances (locally within the same organ, to neighboring cells, or sometimes only to different parts of the same cell) in order to elicit immune defenses.²⁷ There are several families of eicosanoids (including prostaglandins, prostacyclins, leukotrienes, and thromboxanes) that are created by most cell types in all major organ systems. Aside from their roles in inflammation (and anti-inflammation), prostaglandins have a variety of functions in cell growth, kidney function, digestion, and the constriction and dilation of blood vessels. Thromboxanes are important mediators of the blood clotting process. Pro-inflammatory leukotrienes are important for recruiting and activating white blood cells during inflammation, and are best studied for their role in airway constriction and anaphylaxis.

Cells produce eicosanoids using unsaturated fatty acids that are part of their cell membranes. The fatty acid starting materials for eicosanoid synthesis are the essential fatty acids linoleic acid (omega-6) and its derivative arachidonic acid (AA); and alpha-linolenic acid (an omega-3) and its derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). While generalizations about roles of these fatty acids in eicosanoid synthesis should be approached cautiously, the most potent inflammatory eicosanoids are produced from omega-6 fatty acids (linoleic and arachidonic acids). Diets high in omega-3 fatty acids are associated with lower biomarkers of inflammation and cardiovascular disease risk; proposed mechanisms include the production of less inflammatory or anti-inflammatory eicosanoids and through the cyclooxygenase and lipoxygenase enzymes.²⁸

Cyclooxygenases and Lipoxygenases

The eicosanoids require several enzymatic steps to be synthesized from unsaturated fatty acids; the cyclooxygenase (COX) and lipoxygenase (LOX) enzymes catalyze the first steps in these reactions. Cyclooxygenases initiate the conversion of omega-3 and omega-6 derivatives into one of the many prostaglandins or thromboxanes. The interest in COX enzyme metabolism comes from the fact that its inhibition leads to decreased prostaglandin synthesis, and therefore a reduction in inflammation, fever, and pain. The analgesic and anti-inflammatory activity of aspirin and NSAIDs (like ibuprofen and naproxen) is due to their inhibition of COX enzymes. There are two COX enzymes with well-defined roles in humans (COX-1 and COX-2). COX-2 has the most relevance to the inflammatory process; it is normally inactive, but is turned on during inflammation and stimulates this process of inflammation by creating pro-inflammatory prostaglandins and thromboxanes.

Lipoxygenases convert fatty acids into proinflammatory leukotrienes, important local mediators of inflammation. Several potent inflammatory leukotrienes are produced by 5-LOX in mammals. Lipoxygenase enzymes, and the pro-inflammatory factors they produce, have a fundamental role in the inflammatory process by aiding in the recruitment of white blood cells to the site of inflammation. They also stimulate local cells to produce cytokines, which amplifies the inflammatory response.²⁷ Thus, LOX enzymes may be involved in a wide variety of inflammatory conditions, and represent an additional target for anti-inflammatory therapy.

While COX and LOX enzymes are most often associated with pro-inflammatory processes, it is important to remember that both enzymes also produce factors that inhibit or resolve inflammation and promote tissue repair (including the prostacyclins and lipoxins). The proper transition from pro- to anti-inflammatory activities of the COX and LOX enzymes is important for the progression of a healthy inflammatory response.

There are several risk factors which increase the likelihood of establishing and maintaining a low-level inflammatory response.

Age

In contrast to younger individuals (whose levels of inflammatory cytokines typically increase only in response to infection or injury), older adults can have consistently elevated levels of several inflammatory molecules, especially IL-6 and TNF-α.⁹ These elevations are observed even in healthy older individuals. While the reasoning for this age-associated increase in inflammatory markers is not thoroughly understood, it may reflect cumulative mitochondrial dysfunction and oxidative damage, or may be the result of other risk factors associated with age (such as increases in visceral body fat or reductions in sex hormones).

Obesity

Fat tissue is an endocrine organ, storing and secreting multiple hormones and cytokines into circulation and affecting metabolism throughout the body. For example, fat cells produce and secrete both TNF-α and IL-6, and visceral (abdominal) fat can produce these inflammatory molecules at levels sufficient to induce a strong inflammatory response.^29,30 Visceral fat cells can produce three times the amount of IL-6 as fats cells elsewhere,³¹ and in overweight individuals, may be producing up to 35% of the total IL-6 in the body.³² Fat tissue can also be infiltrated by macrophages, which secrete pro-inflammatory cytokines. This accumulation of macrophages appears to be proportional to body mass index (BMI), and appear to be a major cause of low-grade, systemic inflammation and insulin resistance in obese individuals.^33,34

Diet

A diet high in saturated fat is associated with higher pro-inflammatory markers, particularly in diabetic or overweight individuals.^35,36 This effect was absent in healthy individuals.^37-39 Diets high in synthetic trans fats (such as those produced by hydrogenation) have been associated with increases in inflammatory markers (IL-6, TNF-α, IL-8, CRP) in some studies,^40,41 but had no effect in others.^42,43 The increases in markers of inflammation due to synthetic trans fats may be more pronounced in overweight individuals.⁴²

General dietary over-consumption is a major contributor to inflammation and other detrimental age-related processes in the modern world. Therefore, eating a calorie-restricted diet is an effective means of relieving physiologic stressors. Indeed, several studies show that calorie restriction provides powerful protection against inflammation.^44,45 For more information about the metabolic benefits of eating fewer calories, readers should refer to the “Caloric Restriction” protocol.

Low Sex Hormones

Amongst their many roles in biology, sex hormones also modulate the immune/inflammatory response. The cells that mediate inflammation (such as neutrophils and macrophages) have receptors for estrogens and androgens that enable them to selectively respond to sex hormone levels in many tissues.⁴⁶ A notable example is that of osteoclasts, the macrophages that reside in skeletal tissue and are responsible for breaking down and recycling old bone. Estrogens turn down osteoclast activity. Following menopause, lowered estrogen levels cause these bone depleting cells to maintain their activity, breaking down bone faster than it is rebuilt. This is one of the factors in the progression of osteoporosis.

Experiments in cell culture have demonstrated that testosterone and estrogen can repress the production and secretion of several pro-inflammatory markers, including IL-1β, IL-6, TNF-α, and the activity of NF-κB.^47-49 These observations have been corroborated by observational studies that have linked lower testosterone levels in elderly men to increases in inflammatory markers (IL-6 and IL-6 receptor).^50,51 Several studies have shown an increase in inflammatory IL-1β, IL-6, and TNF-α following surgical or natural menopause.^9,52 Conversely, the preservation of sex hormone levels is associated with reductions in the risk of several inflammatory diseases, including atherosclerosis, asthma in women, and rheumatoid arthritis in men.⁴⁶ Hormone replacement therapy (HRT) may partially exert its protective effects through an attenuation of the inflammatory response. Reductions in the risks of coronary heart disease and inflammatory bowel disease in some individuals, as well as levels of some circulating inflammatory cytokines (including IL-1B, IL-8, and TNF-α) has been observed in some studies of women on HRT.^53-55

Smoking

Cigarette smoke contains several inducers of inflammation, particularly reactive oxygen species. Chronic smoking increases production of several pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8), while simultaneously reducing production of anti-inflammatory molecules.56 Smoking also increases the risk of periodontal disease, an independent risk factor for increasing systemic inflammation.⁵⁷

Sleep Disorders

Production of inflammatory cytokines (TNF-α and IL-1β) appears to follow a circadian rhythm and may be involved in the regulation of sleep in animals and humans.⁵⁸ Disruption of normal sleep can lead to daytime elevations of these pro-inflammatory molecules. Plasma levels of TNF-α and/or IL-6 were elevated in patients with excessive daytime sleepiness, including those with sleep apnea and narcolepsy.⁵⁸ These elevations in cytokines were independent of BMI or age,^59,60 although persons with higher visceral body fat were more likely to have sleep disorders.⁶¹

Other Inciting Factors

Periodontal disease can produce a systemic inflammatory response that may affect several other systems, such as the heart and kidneys.^62,63 It is by this mechanism that periodontal disease is thought to be a risk factor for cardiovascular diseases.⁶⁴

Stress (both physical and emotional) can lead to inflammatory cytokine release (IL-6); stress is also associated with decreased sleep and increased body mass (stimulated by release of the stress hormone cortisol), both of which are independent causes of inflammation.⁶⁵

The maintenance of a proper inflammatory response may also involve the central nervous system. The recently identified vagal immune reflex senses inflammatory molecules through a network of nerves (branches of the vagus nerve), and sends this information to the brain. If the brain determines that the inflammatory response is too great, it sends signals to the site(s) of inflammation to attenuate the response.⁶⁶ Preliminary data suggest depressed nerve activity may be associated with exaggerated inflammatory responses seen in sepsis.⁶⁷ Smoking, itself a risk factor for inflammation, also decreases activity of the vagus nerve.⁶⁸

Cardiovascular Diseases (CVD)

Inflammation is an integral part of atherosclerosis (recall that oxidized low-density lipoprotein cholesterol stimulates the inflammatory response). Circulating inflammatory cytokines are predictive of peripheral arterial disease, heart failure, atrial fibrillation, stroke, and coronary heart disease.^9,26

Cancer

Several studies have established links between chronic low-level inflammation and many types of cancer, including lymphoma, prostate, ovarian, pancreatic, colorectal and lung.^7,76 There are several mechanisms by which inflammation may contribute to carcinogenesis, including alterations in gene expression, DNA mutation, epigenetic alterations, promotion of tumor vascularization, and the expression of pro-inflammatory cytokines that have roles in cancer cell proliferation.^7,77

Diabetes

The infiltration of macrophages into fat tissue and their subsequent release of pro-inflammatory cytokines into circulation occur at a greater rate in type II diabetics than in non-diabetics.^33,35,78 Pro-inflammatory cytokines clearly decrease insulin sensitivity.²

Age-Related Macular Degeneration (AMD)

An evaluation of 11 population-based studies encompassing over 41,000 patients demonstrated a clear association between elevated serum CRP levels (> 3 mg/L) and the incidence of late onset AMD.⁷⁹ The risk of AMD in these high-CRP patients was increased over 2-fold compared with patients with CRP levels < 1 mg/L.

Chronic Kidney Disease (CKD)

The chronic, low-grade inflammation in CKD can lead to the retention of several pro-inflammatory molecules in the blood (including cytokines, AGEs, and homocysteine).⁶ The reduced excretion of pro-inflammatory factors by the diseased kidney can accelerate the progression of chronic inflammatory disturbances elsewhere in the body, such as the cardiovascular system.

Osteoporosis

Inflammatory cytokines (TNF-α, IL-1β, IL-6) are involved in normal bone metabolism. Osteoclasts, the cells that break down (resorb) bone tissue, are a type of macrophage and can be stimulated by pro-inflammatory factors. Systemic elevations in pro-inflammatory cytokines push bone metabolism towards resorption, and have been observed to induce bone loss in persons with periodontal disease, pancreatitis, inflammatory bowel disease, and rheumatoid arthritis.³ An increase in the levels of inflammatory cytokines is also a mechanism by which menopause stimulates bone loss.

Depression

There is a small, but significant association between elevated IL-6 and CRP in depressed patients, which has been observed in many population studies.⁸⁰ It is unclear whether inflammation leads to stress or vice versa, and there is data supporting both hypotheses.^81,82

Cognitive Decline

Several observational studies have linked chronic low-level inflammation in older adults to cognitive decline and dementia, including vascular dementia and Alzheimer’s disease.⁹ One study found people with the highest CRP and IL-6 levels (> 2.4 pg/mL) had a ~30‒40% increased risk of cognitive decline compared to those with the lowest levels (< 1.4 pg/mL).83 Inflammatory markers can be elevated before the onset of cognitive dysfunction, indicating their potential relevance as a prognostic tool in high-risk individuals.⁹

Others

Elevations in circulating inflammatory cytokines are associated with several other conditions, both inflammatory (rheumatoid arthritis, IBD/Crohn’s disease, pancreatitis) and non-inflammatory (anemia, fibromyalgia, frailty, sarcopenia/cachexia/muscle wasting).^4,5,84-86 Again, whether inflammation incites these conditions or results from them is unclear, and requires further investigation.

Chronic inflammation or para-inflammation is generally not treated on its own by mainstream physicians. Interventions in conventional medicine are usually only undertaken when the inflammation occurs in association with another medical condition (such as arthritis). Currently, conventional preventive medical approaches to inflammation are limited to the use of CRP blood testing to predict cardiovascular disease in high-risk subjects, and the prophylactic use of drugs like aspirin to inhibit the inflammatory cascade linked to thrombosis (uncontrolled blood clotting). Indeed, the potentially asymptomatic nature of low grade inflammation is such that elevations of pro-inflammatory cytokines may progress undetected for some time, only being discovered after they have had time to cause enough cellular damage to produce disease symptoms. As future studies solidify the association between inflammatory mediators and different diseases, early detection of cytokine aberrations and anti-inflammatory therapy to reduce disease risk may gain more mainstream acceptance.

Testing Blood for Inflammatory Factors The following two blood tests are inexpensive and are good markers of systemic inflammation. They can be used to detect the presence of chronic inflammation and monitor the success or failure of various anti-inflammatory regimens: Pro-Inflammatory Marker Optimal Ranges High-sensitivity C-reactive protein (CRP) Under 0.55 mg/L in men Under 1.0 mg/L in women Fibrinogen 200‒300 mg/dL The following blood tests are expensive and help identify specific factors that are causing systemic inflammation: Cytokine Testing Normal Ranges (LabCorp) Tumor necrosis factor-alpha (TNF-α) <8.1 pg/mL Interleukin-1 beta (IL-1β) <15.0 pg/mL Interleukin-6 (IL-6) 2‒29 pg/mL Interleukin-8 (IL-8) <32.0 pg/mL

Pentoxifylline

Pentoxifylline is a drug used to treat conditions involving poor circulation to the brain, limbs, and other areas perfused by small blood vessels. The drug effectively decreases blood viscosity and improves peripheral tissue oxygenation. Pentoxifylline acts as a phosphodiesterase inhibitor and has immunomodulatory and anti-inflammatory actions.¹ Preclinical studies have shown that pentoxifylline modulates TNF-α signaling and enhances nitric oxide synthase activity as well.^91,286 Pentoxifylline has been studied in a wide range of conditions, ranging from diabetic complications and non-alcoholic liver disease to endometriosis and cardiac surgery.^87-90

In a randomized clinical trial, 400 mg of pentoxifylline taken twice daily for 12 months significantly suppressed hs-CRP, fibrinogen, and TNF-α levels in patients with chronic kidney disease. And subjects’ renal function did not change with treatment whereas the control group worsened.⁹² Administered at the same dose for one month to 30 diabetic individuals with high blood pressure, pentoxifylline reduced hs-CRP levels by 20% and improved erythrocyte sedimentation rate (a measure of inflammatory tendency of a blood sample) by 18%. Plasma antioxidant status was increased as well, as evidenced by a 20% reduction in malondialdehyde levels (a measure of oxidative stress) and a nearly 5% increase in glutathione levels.⁹⁵ Pentoxifylline, at dosages ranging from 400 mg once daily to three times per day, has also demonstrated anti-inflammatory effects in clinical studies^287-290; a meta-analysis of 15 randomized controlled trials including 739 participants concluded that these dosages of pentoxifylline significantly reduced TNF-α and hs-CRP levels.²⁹¹ And in a small clinical study, pentoxifylline administered intravenously to patients with sepsis demonstrated some benefit, including decreasing TNF-α levels.²⁹² However, a different small trial with intravenous pentoxifylline did not show a reduction in TNF-α levels, although it did improve cardiopulmonary dysfunction.²⁹³ Intravenous pentoxifylline has also been studied in septic infants, and has generally been found to offer some benefits as an adjunct to antibiotic treatment.^294,295

Cabergoline

Cabergoline, a derivative of ergot, binds the D2 dopamine receptor leading to sustained decreases in prolactin secretion from the pituitary gland. It is used as a first-line treatment for pituitary adenomas and has been used in the treatment of Parkinson disease.²⁹⁶ Cabergoline has been reported to have anti-inflammatory activity; in an animal study, cabergoline protected the blood–brain barrier and reduced lipopolysaccharide-induced gene expression of TNF-α and IL-6.²⁹⁷

Prolactin levels have been linked to inflammatory status in males,²⁹⁸ and high prolactin levels may be a risk factor for delirium in patients with sepsis, a condition that involves a pronounced systemic inflammatory response.²⁹⁹ Prolactin levels also appear to be increased in synovial and periodontal tissues in patients with rheumatoid arthritis and periodontitis, respectively—two common chronic inflammatory diseases.³⁰⁰

A clinical trial in 15 patients with hyperprolactinemia found that 12 weeks of cabergoline treatment at 0.5–1 mg twice weekly reduced hs-CRP, prolactin, and insulin levels.³⁰¹ In another small clinical study, 21 patients with prolactinoma were given 0.5 mg/day cabergoline and tapered as necessary over six months. Insulin sensitivity, homocysteine, and hs-CRP all improved, although independently of prolactin levels.³⁰² Further clinical studies are necessary to elucidate prolactin and cabergoline’s potential roles in inflammatory conditions.

Metformin

The regulation of energy metabolism and inflammation are closely associated; this is evidenced by the co-incidence of metabolic disorders (obesity, diabetes) and low-grade inflammation.⁹⁶ Metformin may reduce the activity of inflammatory cytokines by increasing the production of IL-1βreceptor antagonist (IL1Rn), a protein factor which interferes with pro-inflammatory signaling of IL-1β.⁹⁷ It may also promote favorable CRP levels, although not to the same extent as weight loss.^96,98 A randomized controlled trial of hypertensive and dyslipidemia patients taking 1,700 mg/day of metformin for 12 weeks demonstrated a 26.7% reduction in IL-6 and 8.3% reduction in TNF-α from baseline levels, a degree of reduction similar to that of the potent statin drug rosuvastatin (Crestor).⁹⁹ The anti-inflammatory effects of metformin appear to be rapid; reductions in circulating TNF-α, IL-1β, CRP, and fibrinogen were observed after only 30 days in a larger study of 128 type II diabetic patients with dyslipidemia.¹⁰⁰

Aspirin

Aspirin has been used as an anti-inflammatory therapy long before the molecular mechanics of inflammation had been discovered; it is now well characterized as an inhibitor of cyclooxygenase enzymes. The modification of COX molecules by aspirin has important implications for cardiovascular health. Blood platelets use cyclooxygenase to produce thromboxane A2, a pro-inflammatory molecule that is an important signal during the initial stages of the clotting process. The inhibitory effect of aspirin on COX enzymes in platelets can partially explain its protective effects against the complications of several disorders, including hypertension, heart attack, and stroke.¹⁰¹ Aspirin's inhibition of cyclooxygenase also helps explain its potential effect on cancer risk reduction as observed in several studies,^102-105 as COX-2 also appears to have roles in increasing the proliferation of mutated cells, tumor formation, tumor invasion, and metastasis, and may contribute to drug resistance in some cancers.¹⁰⁶ Aspirin has also been shown to reduce the activity of NF-kB in vitro,¹⁰⁷ and lower levels of multiple inflammatory markers (TNF-α, CRP, IL-6) in patients with cardiovascular disease.^108-111

Unlike many other NSAIDs, the effects of aspirin on COX enzymes are permanent for the life of the COX enzyme. Interestingly, it appears that rather than rendering the enzyme inactive, aspirin modifies the function of COX. Aspirin stops the enzyme from producing pro-inflammatory prostaglandins, and enables it to begin producing anti-inflammatory molecules called resolvins.¹¹²

Low-Dose Statin Drugs

Statins are thought to reduce inflammation by a mechanism distinct from their effects on cholesterol metabolism; they interfere with the function of cytokine receptors on the surface of white blood cells. Therefore, pro-inflammatory signals in the blood are unable to provoke a response from white blood cells, and they are prevented from further stimulating inflammation.^113,114 Results of the JUPITER trial presented the strongest evidence for statins as anti-inflammatory therapy. In this study of over 17,000 healthy middle-aged men and women with elevated levels of the inflammatory marker CRP but normal levels of blood lipids, 20 mg/day of rosuvastatin reduced CRP levels by over half, in addition to reducing heart attack and stroke incidence.¹¹⁵ Smaller studies have looked at the effect of statins on other inflammatory markers as well. A randomized controlled trial of hypertensive and dyslipidemia patients taking a lower dose (10 mg/day) of rosuvastatin for 12 weeks demonstrated a ~22% reduction in IL-6 and 13% reduction in TNF-α from baseline levels.⁹⁹ A second uncontrolled study of simvastatin demonstrated more modest reductions in IL-6, but no changes in TNF-α from the statin treatment.¹¹⁶ To generate a substantial anti-inflammatory effect using statin drugs alone requires a high dose that is more likely to induce side effects than lower dose statin therapy.

Inflammation itself is not a disease, but is featured, to varying degrees, in adverse health conditions. Information on strategies and research regarding the reduction of inflammation characteristic to specific health conditions are featured in their respective Life Extension protocols: "Allergies," "Macular Degeneration," "Cancer Adjuvant Therapy," "Atherosclerosis and Cardiovascular Disease," "Gout and Hyperuricemia," "Inflammatory Bowel Disease (Crohn’s and Ulcerative Colitis)," "Osteoarthritis," "Arthritis–Rheumatoid," and "Osteoporosis." What follows is a summary of dietary and supplemental approaches to addressing general chronic inflammation and para-inflammation. As many types of general inflammation often occur without additional symptoms, most of the strategies listed below are based on their ability to reduce circulating inflammatory cytokines, the hallmark of the para-inflammatory state.

Macronutrients and Energy Balance

Macronutrient content (particularly the types and levels of carbohydrates and fats) can have a significant effect on the progression of inflammation (as measured by increases in pro-inflammatory markers). Diets with relatively high glycemic index (GI) and glycemic load (GL) have been associated with elevated risk of coronary heart disease, stroke, and type 2 diabetes mellitus, particularly among overweight individuals, and have been associated with modest increases in proinflammatory markers in multiple studies.¹¹⁷ In a study of over 18,000 healthy women ≥45 years old without diagnosed diabetes, high GI and GL diets resulted in a small but significant increase in hs-CRP (+12% for high GI) over low GI diets.¹¹⁸ In the Danish Hoorne study,¹¹⁹ for every 10 unit increase in dietary glycemic index, circulating CRP was increased by 29%. As discussed previously, some dietary fats (particularly saturated and synthetic trans fats) increase inflammation occurrence, while omega-3 polyunsaturated fats appear to be anti-inflammatory.⁴⁰

Since fat tissue (especially abdominal fat) expresses inflammatory cytokines, obesity can be a major cause of low-grade, systemic inflammation.^33,34 Thus, it is important that total energy intake be proportional to energy expenditure, to avoid the deposition of abdominal fat. Obesity-induced increases in inflammatory cytokines appear to be reversible with fat loss.¹²⁰ In a dramatic example, weight loss (by adjustable gastric banding) in a group of 20 severely obese individuals reduced IL-6 by 22% and CRP by almost half.¹²¹

An inflammatory index, developed by a group from the Arnold School of Public Health at the University of South Carolina, scored 42 common dietary constituents based on their ability to raise serum CRP.¹²² Constituents (such as saturated fat, tea polyphenols, or vitamin D) were given either a positive (anti-inflammatory) or negative (pro-inflammatory) score, the magnitude of which was weighted based on the volume of inflammation research on the isolated ingredient. Human clinical data was weighted more than animal data, and clinical trials more than observational studies. The scores were then verified by comparing them to nutrient intakes and CRP levels from a group of 494 volunteers over the course of one year. Amongst the most anti-inflammatory nutrients (based on the model and study data) are magnesium, beta-carotene, turmeric (curcumin), genistein, and tea; the most pro-inflammatory included carbohydrates, total- and saturated fat, and cholesterol. The index may provide a useful metric for accessing the overall inflammatory potential of an individual diet.

Exercise

Energy expenditure through exercise lowers multiple cytokines and pro-inflammatory molecules independently of weight loss. While muscle contraction initially results in a pro-inflammatory state, it paradoxically lowers systemic inflammation. This effect has been observed in dozens of human trials of exercise training in both healthy and unhealthy individuals across many age groups.¹²³

Fiber

In an analysis of seven studies on the relationship between weight loss and hs-CRP, increased fiber consumption correlated with significantly greater reductions in hs-CRP concentrations. In these studies, daily fiber intakes ranging from 3.3 to 7.8 grams/MJ (equivalent to about 27 to 64 grams/day for a standard 2,000 kcal diet) reduced CRP from 25%‒54% in a dose-dependent fashion. These results should be interpreted carefully, as only two of the seven studies were specifically designed to examine the effects of fiber independently.¹²⁰ The Women’s Health Initiative failed to detect an effect of fiber consumption on hs-CRP, but found that greater intake of dietary soluble and insoluble fiber (over 24 grams/day) was associated with lower levels of IL-6 and TNF-α.¹²⁴

Magnesium. In two large observation studies (the Women’s Health Initiative and Harvard Nurses Study), greater magnesium intake was associated with lower hs-CRP, IL-6, and TNF-α receptor, a measure of TNF-α activity.^117,125 Data from the Multi-Ethnic Study of Atherosclerosis failed to find significant differences in IL-6 or CRP levels between individuals with the highest and lowest magnesium intakes, but did find a significant association between greater dietary magnesium and the lower levels of the inflammation-associated proteins homocysteine and fibrinogen.¹²⁶ Magnesium was rated as the most anti-inflammatory dietary factor in the Dietary Inflammatory index, which rated 42 common dietary constituents on their ability to reduce CRP levels based on human and animal experimental and observation data.¹²²

Vitamin D. Vitamin D appears to exert anti-inflammatory activity by the suppression of pro-inflammatory prostaglandins, and inhibition of the inflammatory mediator NF-κB.¹²⁷ Although intervention studies of its anti-inflammatory activity in humans are lacking, several observational studies suggest vitamin D deficiency may promote inflammation. Vitamin D deficiencies are more common amongst patients with inflammatory diseases (including rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and diabetes) than in healthy individuals.¹²⁸ They also occur more frequently in populations that are prone to low-level inflammation, such as obese individuals and the elderly.¹²⁹ Vitamin D levels can drop following surgery (a condition associated with acute inflammation), with a concomitant rise in CRP.¹³⁰ Low vitamin D status was associated with elevated CRP in a study of 548 heart failure patients,¹³¹ and with increases in IL-6 and NF-κB in a group of 46 middle-aged men with endothelial dysfunction.¹³²

Vitamin E. Vitamin E functions as an antioxidant in the body. Specifically, vitamin E is incorporated into low-density lipoprotein (LDL) particles and protects them against oxidative damage; it seems to guard against atherosclerosis via other mechanisms as well.¹³³ The gamma-tocopherol form of vitamin E appears to complement the anti-inflammatory action of alpha-tocopherol. Gamma-tocopherol has been shown to inhibit COX-2 and attenuate IL-1β signaling.^134,135 In a small clinical trial on subjects with metabolic syndrome, the combination of gamma-tocopherol and alpha-tocopherol effectively suppressed C-reactive protein and TNF-α levels compared to placebo.¹³⁶ In this study, the combination of both tocopherols performed better than either alone, prompting the investigators to remark "the combination of [alpha-tocopherol] and [gamma-tocopherol] supplementation appears to be superior to either supplementation alone on biomarkers of oxidative stress and inflammation and needs to be tested in prospective clinical trials..."

Zinc and selenium. Zinc- and selenium-containing antioxidant proteins (such as superoxide dismutase and glutathione peroxidase) reduce reactive oxygen species (free radicals), which indirectly inhibits NF-κB activity and prevents the production of several inflammatory enzymes and cytokines. Zinc can also inhibit NF-κB in a more direct manner.^137,138 Zinc supplementation is associated with decreases in inflammation in populations that are prone to zinc deficiency, such as children and the elderly.^139,140 Low level inflammation and circulating pro-inflammatory factors (CRP, TNF-α, IL-6, and IL-8) were reduced in elderly subjects by moderate zinc supplementation in several studies.^141-143 Like zinc, selenium deficiencies are common in chronic inflammatory states associated with disease (such as sepsis),¹⁴⁴ where selenium supplementation has been associated with reductions in inflammation and better patient outcomes.¹³⁸

Other Dietary Factors

Specialized pro-resolving mediators. Specialized pro-resolving mediators (SPMs) are cell-signaling molecules derived from the metabolism of polyunsaturated fatty acids. They play an important role in resolution of the inflammatory response.^250,251 SPMs include lipoxins, resolvins, protectins, maresins, and their precursors; they do not merely inhibit inflammation, but actively resolve inflammatory processes to help return tissues to a normal state.²⁵¹ SPMs recruit macrophages to clear cellular debris, which allows for the recovery of healthy cells²⁵²; rejuvenate tissue damaged by inflammation²⁵³; and restore the balance between anti-inflammatory cytokines and pro-inflammatory cytokines.^254,255

Chronic inflammation contributes to aging and degeneration, and pro-resolving mediators may help reduce the risk of some diseases associated with inflammation and aging.^251,256-259 Research on obese mice suggest low-grade inflammation drives metabolic disturbances, and SPM precursors may mitigate obesity complications.²⁵⁸ Another study demonstrated that 1‒5 mg/kg/day of the SPM resolvin E1 reduced atherosclerotic lesions in mice fed a high-cholesterol diet for nine weeks.²⁵⁷

SPMs derived from marine oils help support the body’s efficient resolution of the inflammatory response. The body creates pro-resolving mediators from omega-3 fatty acids, including EPA and DHA²⁶⁰; however, they are not completely converted into SPMs. Omega-3s and SPMs also have distinct roles in the body.

A novel clinical trial was conducted to better understand the effect of supplementation with EPA and DHA on SPM plasma concentrations of lipid metabolites. A total of 21 patients with chronic inflammation were randomized to sequentially receive 3 grams/day EPA or DHA for 10 weeks; there was a 10-week washout period in between. This study also included an ex vivo analysis, which evaluated how SPMs derived from EPA and DHA differed in their effects on inflammatory cells (monocytes).²⁷⁰

The results showed both EPA and DHA increased plasma levels of SPMs and SPM precursors in their own manner. In the ex vivo portion of the study, monocytes (macrophage precursor cells) derived from the participants’ blood samples were stimulated in vitro with a toxin (LPS) to induce an inflammatory response. The genetic expression of pro-inflammatory TNF-α and monocyte chemoattractant protein-1 (MCP-1) were decreased by both EPA and DHA in vitro. EPA had no effect on pro-inflammatory IL-6 expression; however, DHA decreased it. DHA lowered anti-inflammatory IL-10 expression; however, EPA increased it. Interestingly, DHA inhibited individual pro-inflammatory cytokines more potently than EPA, but EPA more effectively balanced the ratio of inflammatory cytokines to the anti-inflammatory cytokine IL-10.

These results provide new insight into the independent effects of EPA and DHA and suggest both omega-3s play important roles in inflammation resolution.

Resveratrol and pterostilbene. The exact mechanism by which resveratrol exerts anti-inflammatory activity has not been established, although it inhibits a variety of pro-inflammatory compounds (cyclooxygenase, TNF-α, IL-1β, IL-6, NF-κB) in animal models and human cell culture.^145,146 The related compound pterostilbene has demonstrated similar inhibition of inflammatory markers in cell culture.¹⁴⁷ Modulation of the inflammatory immune response likely contributes to resveratrol’s protective role in animal models of heart disease, cancer, acute pancreatitis and inflammatory bowel disease.¹⁴⁸ Resveratrol may be protective against general, low-level para-inflammation as well: when taken with a single high-fat, high-carbohydrate meal (930 kcal), resveratrol (100 mg) prevented the sharp post-meal increases in markers of oxidation and inflammation in a small crossover study of 10 healthy volunteers. For example, synthesis of IL-1β increased by 91% over five hours following the test meal; with resveratrol, this increase was significantly less (29%).¹⁴⁹

Curcumin. Extensive in vitro and animal studies have examined the effects of curcumin on experimentally-induced inflammatory diseases (atherosclerosis, arthritis, diabetes, liver disease, gastrointestinal disorders, and cancers) and disease markers (lipoxygenase, cyclooxygenase, TNF-α, IL-1β, NF-κB, and others).^150,151 Fewer human studies have examined curcumin’s effects on patient-oriented outcomes in inflammatory diseases, but most of the small randomized controlled trials of curcumin have consistently shown patient improvements in several inflammatory diseases, including psoriasis, irritable bowel syndrome, rheumatoid arthritis, and inflammatory eye disease.^152,153

Tea polyphenols. The anti-inflammatory effects of green and black tea polyphenols have been substantiated by dozens of in vitro and animal studies.¹⁵⁴ The polyphenols EGCG and theaflavin exert their anti-inflammatory effects through the inhibition of the NF-κB signaling pathway, which decreases expression of several inflammatory proteins (lipoxygenase, cyclooxygenase, TNF-α, IL-1β, IL-6, and IL-8) in cell culture experiments.¹⁵⁵ EGCG also inhibits the production and release of histamine, a key mediator of allergic and inflammatory response, in vitro.¹⁵⁶ In observational studies of tea consumption, >2 cups of tea/day (black or green) was associated with a nearly 20% reduction in CRP compared to non-tea drinkers, and significantly lower levels of two other inflammatory markers (serum amyloid A and haptogen, which are elevated in coronary heart disease).¹⁵⁷ In clinical interventions, black tea appears to be more successful in reducing inflammatory markers than green.¹¹⁷ A 25% reduction in CRP was also observed in a small trial of healthy, non-smoking men consuming a black tea extract (equivalent to four cups of tea/day) for six weeks.¹⁵⁸ A similar average reduction was observed in a larger study of healthy, individuals at high risk for coronary heart disease, but revealed a more dramatic 40‒50% reduction in CRP amongst individuals with the highest starting CRP values (>3 mg/L).¹⁵⁹

Carotenoids. In the Women’s Health and Aging Study, participants with the highest blood levels of α-carotene and total carotenoids were significantly more likely to have the lower IL-6 levels than participants with low carotenoid levels at the onset of the study.¹⁶⁰ Participants with the lowest blood levels of α- and β-carotene, lutein/zeaxanthin, or total carotenoids were more likely to experience increases in IL-6 over a period of two years.

DHEA. Low levels of sex hormones are associated with systemic increases in inflammatory markers⁹; DHEA (dehydroepiandrosterone), an adrenal steroid hormone, is the precursor to the sex steroids testosterone and estrogen. DHEA is abundant in youth, but steady declines with advancing age and may be partially responsible for age-related decreases sex steroids.¹⁶¹ In cell culture and animal models, DHEA can suppress inflammatory cytokine activity, in some cases more effectively than either testosterone or estrogen.¹⁶² Chronic inflammation may itself reduce DHEA levels.¹⁶³ DHEA supplementation in elderly volunteers (50 mg/day for two years) significantly decreased TNF-α and IL-6 levels, as well as lowered visceral fat mass and improved glucose tolerance (both associated with inflammation) in a small study.¹⁶⁴

Fish oil. Fish oil is the best source of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which can only be synthesized to a limited extent in humans. Omega-3 fatty acids have been well studied for their prevention of cardiovascular disease and mortality in tens of thousands of patients; the anti-inflammatory effects of omega-3’s contribute to this activity.¹⁶⁵ They have also proven successful at improving patient outcomes in scores of studies of other inflammatory diseases, particularly asthma, inflammatory bowel disease, and rheumatoid arthritis.^166,167

The association between greater fish oil/omega-3 consumption and reduced systemic inflammation is substantiated by data from several large observational trials. In 855 healthy participants from the Health Professionals Follow-Up Study, omega-3 fatty acid intake was associated with lower plasma levels of markers of TNF-α activity; interestingly, high intake of both omega-3 and omega-6 fatty acids (which are usually assumed to be pro-inflammatory) was associated with the lowest level of inflammation.¹⁶⁸ The Nurses’ Health Study I cohort of 727 women revealed lower concentrations of inflammatory markers (including CRP and IL-6) amongst those in the top 20% of omega-3 consumption, when compared to those who consumed the least amount.¹⁶⁹ In the ATTICA study of over 3,000 Greek men and women without any evidence of cardiovascular disease, participants who consumed over 300 grams of fish per week had, on average, 33% lower CRP, 33% lower IL-6, and 21% lower TNF-α than participants who did not consume fish.¹⁷⁰ In a sample of 5,677 men and women without cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, long-chain omega-3 intake (from fish or supplements) was associated with reduced plasma concentrations of multiple inflammatory markers (including CRP, IL-6, and TNF-α receptor, a measure of TNF-α activity).¹⁷¹

N-acetyl cysteine. Activation of the NF-κB pathway plays a central role in the activation of inflammatory cytokine genes; N-acetyl cysteine (NAC) inhibits NF-κB in cell culture, lowering expression of cytokines such as IL-6 and IL-8.^172,173 Data establishing the effects of NAC on lowering chronic inflammation in humans is limited, but shows promise. NAC supplementation for eight weeks demonstrated modest, but statistically significant decreases in circulating IL-6 levels in patients with chronic kidney disease.¹⁷⁴ The effects were more pronounced in persons with significant inflammation at the start of the study (as measured by hs-CRP). NAC also reduced markers of systemic inflammation in a small study of patients with burn injuries.¹⁷⁵

Boswellia. Boswellia serrata (frankincense) is a traditional anti-arthritic in Ayurvedic medicine; its anti-inflammatory properties have been attributed to the specific inhibition of 5-LOX and reduction in the production of pro-inflammatory leukotrienes by boswellic acids, a constituent of the Boswellia gum resin.¹⁷⁶ In cell culture, both crude and highly purified Boswellia extracts inhibited the production of pro-inflammatory TNF-α and IL-1β.¹⁷⁷ One of the boswellic acids, Acetyl-11-keto-beta-boswellic acid (AKBA), was an inhibitor of NF-κB activity in mice,¹⁷⁸ while a topical mixture of the four most abundant boswellic acids decreased inflammation in a rodent inflammation model.¹⁷⁹ A recent systematic review of human trials of Boswellia for inflammatory conditions revealed that the small number of randomized controlled trials on the extract have produced encouraging results for its use for asthma and osteoarthritis,¹⁸⁰ warranting larger studies to confirm the extract as an effective therapy. Standardized Boswellia extracts (30% AKBA) have been effective in mitigating pain in osteoarthritis patients¹⁸¹; when combined with non-volatile Boswellia oil, the standardized extract (called AprèsFlex, or Aflapin) demonstrated improved activity at a lower concentration.¹⁸² The use of Boswellia extracts for inflammatory bowel diseases has been investigated in multiple clinical trials, although results have been mixed.^183-185

Sesame lignans. The observation that sesame oil could decrease the production of arachidonic acid in fungi and rat liver cells led to the identification of the sesame lignans (sesamin, sesamolin, sesaminol) as specific inhibitors of Δ5 desaturase (delta-5-desaturase), one of the enzymes used in the synthesis of arachidonic acid.¹⁸⁶ By inhibiting Δ5 desaturase, sesame lignans may reduce the synthesis of pro-inflammatory prostaglandin, leukotrienes, and thromboxanes, each of which require arachidonic acid as a starting material.¹⁸⁷ In animal models, diets high in sesame seed oil reduced production of the pro-inflammatory prostaglandins PGE-1 and -2, as well as thromboxane B2.188 In humans, five weeks of sesamin supplementation (39 mg/day) reduced the production of the pro-inflammatory vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE; a product of the enzyme 5-LOX) by 30%.¹⁸⁹ This potential anti-inflammatory property of sesame lignans may partially explain its observed hypotensive (blood pressure-lowering) activity.¹⁹⁰

Bromelain. Typically derived from pineapple stem, bromelain comprises a mixture of proteolytic enzymes. In preclinical research, bromelain has consistently demonstrated a variety of anti-inflammatory properties.^271,272 These anti-inflammatory effects have been attributed to reduced COX-2 activity and decreased prostaglandin synthesis. Bromelain also modulates blood coagulation through its effects on fibrin and fibrinogen.²⁷²

Human trials of bromelain for inflammatory conditions have also yielded promising results.²⁷³ A meta-analysis of four studies found that bromelain reduced swelling and had analgesic and anti-inflammatory effects after dental surgery.²⁷⁴

A month-long open-label study assessed the effects of different dosages of bromelain on mild acute knee pain. Seventy-seven participants who had knee pain for less than three months but were otherwise healthy took either 200 or 400 mg bromelain per day. The participants evaluated their own pain and functionality via standardized questionnaires at baseline and after one month. Compared with baseline, symptom scores improved by 41% in the 200 mg group and 59% in the 400 mg group. Psychological well-being significantly improved in both groups as well.²⁷⁵

A randomized controlled non-inferiority trial compared a standardized enzyme preparation containing bromelain (90 mg, three times daily) plus trypsin and rutoside against the NSAID diclofenac (Voltaren, among others) (50 mg, twice daily) in 103 people with knee osteoarthritis. The investigators found that bromelain performed at least as well as diclofenac on patient-reported assessments of pain and functionality.²⁷⁴

Another randomized trial that enrolled 30 people with symptomatic temporomandibular joint (TMJ) arthritis compared three treatment regimens:

• diclofenac alone (group 1)
• diclofenac plus an enzyme preparation consisting of bromelain (90 mg), trypsin, and rutoside (group 2)
• the enzyme preparation alone (group 3)

The response of groups 1 and 3 were considered equal, again demonstrating that the combination containing bromelain was as effective as diclofenac. However, participants in group 2 had significant improvement in pain and inflammation compared to those treated with diclofenac or oral enzymes alone.²⁷⁶ These findings suggest bromelain and these other ingredients may complement NSAIDs in the management of inflammatory conditions.

A pilot study that enrolled 49 people with osteoarthritis found that consuming a supplement containing a mixture of Boswellia and bromelain for up to six months significantly improved self-reported quality of life scores. The most robust symptomatic improvements were reported for joints most severely affected at baseline.²⁷⁷

In another randomized controlled non-inferiority trial, researchers divided 90 individuals with painful osteoarthritis of the hip into two groups: half received an oral enzyme preparation containing bromelain, trypsin, and rutoside for six weeks, while the other half received the anti-inflammatory drug diclofenac. They found that the bromelain preparation was as effective as diclofenac in standardized scales of pain, stiffness, and physical function, and tended to be better tolerated than the drug comparator. Moreover, the study investigators reported efficacy as “good” or “very good” for 71% of subjects who took the bromelain-containing preparation and 61% of those who took diclofenac.^271,272

Mung bean extract. Mung bean (Vigna radiata) has been used for centuries in Asia as a traditional food and herbal medicine for inflammatory conditions, and modern research is supporting its anti-inflammatory effects.²⁰⁰ Two flavonoids in particular, vitexin and isovitexin, appear to be major contributors to mung bean’s beneficial properties. In one study, mung bean seed coat was found to contain 96% of the vitexin and isovitexin in mung bean, and accounted for 87% of the free radical-neutralizing potential of the bean.²⁰¹ In preclinical studies, vitexin inhibited the production of inflammatory cytokines and maintained levels of defenses against oxidative stress.^202,203 In an animal model of lung injury, isovitexin demonstrated anti-inflammatory effects related to inhibition of cytokines and reduction in oxidative tissue damage.²⁰⁴ Laboratory research has found additional compounds called mung bean seed coat saponins also inhibit cytokine expression.²⁰⁵ One laboratory trial found mung bean coat extract powerfully inhibited both a herpes and respiratory virus to a similar degree as the antiviral drug acyclovir, while in this case inducing antiviral cytokines including TNF-α and IL-6.²⁰⁶

In a trial in obese mice, mung bean seed coat extract significantly reduced inflammatory cytokine levels.²⁰⁷ Mung bean sprout extract demonstrated anti-arthritic activity in arthritic rats,208 and both mung bean seed coat and sprout extracts markedly improved glucose tolerance and metabolic health in diabetic mice.²⁰⁹

In one trial, mice that received mung bean seed coat extract were protected from lethal bacterial infection; the survival rate was 70% in treated mice versus 29.4% in untreated mice. In a laboratory component of the study, mung bean seed coat extract was found to inhibit a protein that mediates lethal systemic inflammation, and the inflammatory cytokine IL-6, while also demonstrating possible direct antibacterial activity.²⁰⁰ In a mouse study, treatment with a fermented mung bean preparation protected mice from cancer while inhibiting inflammation and stimulating immunity.²¹⁰

Black cumin seed oil (Nigella sativa). Black cumin seed oil is an antioxidant and anti-inflammatory agent traditionally used to promote digestive, skin, and liver health.²⁶¹ Research suggests black cumin seed oil balances immune and inflammatory responses, which supports healthy immune system functioning.^262,263 As we age, there is an increase in destructive inflammatory pathways coupled with an impaired immune response, which is associated with chronic diseases such as arthritis, allergies, and cardiovascular disease.²⁶⁴

Black cumin seed oil and its active component thymoquinone are believed to suppress harmful inflammation while supporting the normal immune response required to combat infections and cancer.^263,265 Black cumin seed oil stimulates activity of macrophages and helper T cells.²⁶⁶

In a placebo-controlled trial, 40 women with rheumatoid arthritis took placebo daily for one month followed by 500 mg Nigella sativa twice daily for one month. Arthritis symptoms, including joint swelling and morning stiffness, and disease severity reportedly decreased after treatment.²⁶⁷ In a prospective double-blind study, 66 people with allergic rhinitis were exposed to black cumin seed oil for 30 days. Symptoms of rhinitis, including congestion, itchy nose, and sneezing, decreased after treatment.268 Animal research suggests Nigella supplementation is cardioprotective, as it reduces lipid oxidation and promotes healthy cholesterol levels.²⁶⁹

Mitochondrial Support

Reactive oxygen species generated during mitochondrial respiration contribute to inflammation, as outlined earlier in the protocol. Aging individuals are especially susceptible to mitochondria-related oxidative stress since mitochondria become increasingly dysfunctional with age. Taking steps to support mitochondrial integrity and efficiency can help alleviate some of the systemic oxidative and inflammatory burden caused by poorly functioning mitochondria. Two nutrients, coenzyme Q10 and pyrroloquinoline quinoneare powerful mitochondrial protectants,^211,212 and studies support an anti-inflammatory role for these compounds.

Pyrroloquinoline quinone. Pyrroloquinoline quinone (PQQ) is a cofactor for enzymes critically important for cellular energy homeostasis and redox balance.²¹³ Several studies have shown that PQQ exerts a protective effective during circumstantial mitochondrial stress and increased oxidative load.^212,214 In one study, rats given a diet supplemented with PQQ displayed greater energy expenditure and, remarkably, increased mitochondrial density in liver tissue. PQQ supplemented rats also had lower triglycerides and their hearts were more protected against lack of oxygen than rats that had not been given PQQ.²¹⁵ During periods of limited oxygen supply to cardiac tissue, a dramatic spike in oxidative stress and subsequent inflammation damages cells; the findings from this animal model indicate that PQQ can stave off this inflammatory cell destruction by preserving mitochondrial efficiency in adverse conditions.

Coenzyme Q10. Coenzyme Q10 (CoQ10) is an indispensable intermediary in mitochondrial ATP production. Studies have shown that CoQ10 levels are low during inflammatory conditions. In one investigation, patients with septic shock were found to have CoQ10 levels substantially lower than healthy individuals, and, among patients, lower CoQ10 levels correlated with higher levels of an inflammatory mediator called VCAM.²¹⁶ In an animal model in which rats were given drinking water with added fructose, an experiment that leads to obesity, diabetes, and other inflammatory complications, CoQ10 supplementation attenuated the inflammatory response by decreasing hepatic expression of CRP and other inflammatory mediators.²¹⁷ Laboratory experiments indicate that CoQ10 modulates the expression of several hundred genes, many involved in inflammatory signaling.²¹⁸ Of particular significance, one experiment showed that CoQ10, at physiologically relevant concentrations, was able to blunt induced TNF-α by more than 25% via modulation of the NF-κB signaling pathway.²¹⁸

Guarding Against Inflammatory Glycation Reactions

The role of elevated blood sugar and glycation end products in initiating an inflammatory storm has been discussed. Fortunately, in addition to reducing caloric intake to suppress both fasting and post-meal glucose concentrations, some natural compounds ameliorate the glycation process and may help rein in the sugar-induced inflammatory cascade. Chief among these anti-glycation nutrients are benfotiamine, a member of the B-vitamin family, and carnosine, an amino acid.

Benfotiamine. Benfotiamine has been used to target diabetic complications since the mid 1990’s.²¹⁹ More recent evidence continues to support its use as a powerful protector against blood sugar-induced tissue damage. In a clinical trial, 165 subjects with diabetes were randomized to receive benfotiamine at either 300 or 600 mg per day, or a placebo for six weeks. After the intervention period, those taking benfotiamine exhibited improvements in neuropathic pain in a dose-dependent fashion.²²⁰ An animal model found that benfotiamine relieved neuropathic pain by powerfully suppressing inflammation.²²¹ Moreover, laboratory experiments have shown that, in addition to blocking glycation reactions, benfotiamine may regulate inflammation more directly by modulating COX and LOX enzyme activity.²²²

Carnosine. Carnosine exerts a range of favorable biochemical effects within the body; it powerfully blunts glycation reactions and eases oxidative stress.²²³ In addition, several experiments have revealed a marked ability of carnosine to suppress inflammation in various cell types.^224-226 Unfortunately, carnosine levels decline as much as 63% between ages 10 and 70.²²⁷ Furthermore, in patients with type II diabetes, skeletal muscle carnosine content is markedly lower than in healthy control subjects.²²⁸ When carnosine is administered as a supplement to animals with chemically-induced diabetes, it is able to protect delicate retinal cells from inflammatory complications related to high blood sugar.²²⁹

Gynostemma pentaphyllum. Gynostemma pentaphyllum (G. pentaphyllum) is used in Asian medicine to treat several health conditions, including dyslipidemia, type 2 diabetes, and inflammation.²³⁰ Its effects are due, at least in part, to its ability to activate a critical enzyme called adenosine monophosphate-activated protein kinase (AMPK). This enzyme, which affects glucose metabolism and fat storage, has been called a "metabolic master switch" because it controls numerous pathways related to extracting energy from food and storing and distributing that energy throughout the body.²³¹

Being overweight has a significant effect on AMPK activation and chronic inflammation; it suppresses AMPK activation, leading to abdominal fat deposits which, in turn, activate systemic inflammation. At the same time, inflammation itself suppresses AMPK activation, creating a viscous circle.²³²

Yet greater AMPK activation contributes to weight loss and can suppress inflammation.^233-235 In addition, increased AMPK activation is associated with reduced liver fat accumulation, another source of inflammatory chemicals.²³⁶

Evidence demonstrate the anti-inflammatory effects of G. pentaphyllum. In one laboratory study, researchers found extracts of the herb significantly inhibited several inflammatory chemicals, including TNF-α, interleukin-6, and COX-2 mRNA.²³⁷ Another study in 24 patients with type 2 diabetes found drinking a tea made with the herb for 12 weeks significantly reduced insulin resistance, which is a key contributor to systemic inflammation.^2,238

Hesperidin. Hesperidin and related flavonoids are found in a variety of plants, but especially in citrus fruits, particularly their peels.^239,240 Digestion of hesperidin produces a compound called hesperetin along with other metabolites. These compounds are powerful free radical scavengers and have demonstrated anti-inflammatory, insulin-sensitizing, and lipid-lowering activity.^241,242 Findings from animal and in vitro research suggest hesperidin’s positive effects on blood glucose and lipid levels may be related in part to activation of the AMP-activated protein kinase (AMPK) pathway.^243-245 Accumulating evidence suggest hesperidin may help prevent and treat a number of chronic diseases associated with aging.²⁴¹

Hesperidin may protect against diabetes and its complications, partly through activation of the AMPK signaling pathway. Coincidentally, metformin, a leading diabetes medication, also activates the AMPK pathway. In a six-week randomized controlled trial on 24 diabetic participants, supplementation with 500 mg of hesperidin per day improved glycemic control, increased total antioxidant capacity, and reduced oxidative stress and DNA injury.²⁴⁶ Using urinary hesperetin as a marker of dietary hesperidin, another group of researchers found those with the highest level of hesperidin intake had 32% lower risk of developing diabetes over 4.6 years compared to those with the lowest intake level.²⁴⁷

In a randomized controlled trial, 24 adults with metabolic syndrome were treated with 500 mg of hesperidin per day or placebo for three weeks. After a washout period, the trial was repeated with hesperidin and placebo assignments reversed. Hesperidin treatment improved endothelial function, suggesting this may be one important mechanism behind its benefit to the cardiovascular system. Hesperidin supplementation also led to a 33% reduction in median levels of the inflammatory marker hs-CRP, as well as significant decreases in levels of total cholesterol, apolipoprotein B (apoB), and markers of vascular inflammation, relative to placebo.²⁴⁴ In another randomized controlled trial in overweight adults with evidence of pre-existing vascular dysfunction, 450 mg per day of a hesperidin supplement for six weeks resulted in lower blood pressure and a decrease in markers of vascular inflammation.²⁴⁸ Another controlled clinical trial included 75 heart attack patients who were randomly assigned to receive 600 mg hesperidin per day or placebo for four weeks. Those taking hesperidin had significant improvements in levels of high-density lipoprotein (HDL) cholesterol and markers of vascular inflammation and fatty acid and glucose metabolism.²⁴⁹