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.

Systemic inflammation depends on pro-inflammatory communication between damaged or infected cells and immune cells, as well as between different types of immune cells. A broad array of molecules participate in the inflammatory signaling network. For example, cytokines are a large family of circulating molecules produced by virtually every cell in the body, including immune cells, to regulate inflammation.³⁰³ Eicosanoids, molecules made from polyunsaturated fatty acids (PUFAs) in the cell membrane, influence local immune activity by regulating intracellular inflammatory signaling.³⁰⁴ Blood levels of key cytokines and eicosanoids can be measured to assess the degree of systemic inflammation. In addition, certain enzymes and proteins involved in synthesizing, regulating, or responding to inflammatory messengers can be useful indicators of inflammatory status.³⁰⁵

The following section covers several of the inflammatory factors that can participate in chronic, systemic inflammation and which can be measured through lab testing. This list is presented in alphabetical order.

Blood Tests

The following blood tests for markers of systemic inflammation are used to assess inflammatory status. They can also be useful for monitoring treatment response to anti-inflammatory therapies, including diet and lifestyle changes, nutrient supplements, and condition-appropriate medications.^306-309

Table 1: Lab Tests for Assessing Chronic Inflammation

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.

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

Black Cumin Seed Oil

Reported dosage: Approximately 1,300–2,300 mg daily

Black cumin (Nigella sativa) has a long history of use as a culinary herb and a traditional medicine for treating a wide range of conditions such as headaches, joint pain, back pain, asthma, skin problems, and high blood pressure. Research suggests black cumin seed, its oil, and its main active constituent thymoquinone can help balance immune and inflammatory responses and have antioxidant, antimicrobial, and anticancer properties.⁴³²

Numerous randomized controlled trials have confirmed the anti-inflammatory effect of black cumin. For example, in one randomized controlled trial involving 106 subjects with osteoarthritis of the knee, 2.5 mL of black cumin seed oil (about 2.3 grams) three times daily for one month improved pain and arthritis index scores and reduced the need for pain medications better than placebo.⁴³³ In another randomized placebo-controlled trial in 60 patients with coronary artery disease, 2 grams of black cumin seed oil daily for eight weeks reduced blood levels of adhesion molecules, which play a key role in immune cell migration during the inflammatory process compared with a sunflower oil placebo.⁴³⁴

In a meta-analysis of 20 randomized controlled trials involving a total of 1,086 participants, black cumin (mean dosage approx.1,745 mg/day) was found to reduce levels of CRP and TNF-α, but not IL-6, and improve indicators of oxidative stress.⁴³⁵ Another meta-analysis pooled findings from 16 randomized controlled trials involving 1,033 subjects with metabolic syndrome and associated cardiometabolic conditions (eg, obesity, type 2 diabetes, hypertension). The analysis found black cumin, at daily doses ranging from 900–2,300 mg, decreased levels of CRP, TNF-α, and IL-6, and reduced oxidative stress.⁴³⁶ An umbrella analysis that incorporated findings from seven meta-analyses found, overall, black cumin effectively reduced CRP and TNF-α levels and improved markers of oxidative stress. The dosages used in the studies in the included meta-analyses ranges from 1,300–1,900 mg daily.⁴³⁷ Furthermore, multiple clinical trials have reported black cumin can improve markers of cardiometabolic health, including blood lipids and markers of glycemic control. Dosages reported in the trials vary widely, but the median reported dosage was about 2,000 mg/day.⁴³⁸

Probiotics

Reported dosage: Approximately 4 billion to 35 billion colony forming units (CFUs) daily

Healthy gut bacteria regulate local and systemic immune function by interacting with epithelial and immune cells in the intestinal walls.⁴³⁹ They also produce short-chain fatty acids (SCFAs) that promote balanced immune function. SCFAs like butyrate, propionate, and acetate can affect immune cell activity by suppressing expression of inflammatory cytokines and increasing expression of anti-inflammatory cytokines.⁴⁴⁰ Probiotic supplements contain microorganisms that can have similar beneficial effects and encourage a healthy gut microbiome.^441,442 An umbrella analysis of findings from 39 meta-analyses of randomized controlled trials found treatment with probiotics reduced CRP, TNF-α, and IL-6 levels in patients with a variety of chronic inflammatory disorders. Most of the trials used supplements containing mixed probiotic strains of Lactobacillus, Bifidobacterium, and/or Streptococcus species and used daily doses between about 4 billion and 35 billion CFUs.⁴⁴³

Resveratrol and Pterostilbene

Reported dosage: 500–3,000 mg daily

Resveratrol is a type of polyphenolic compound known as a stilbene. It has demonstrated antioxidant, anti-inflammatory, and anti-aging activities that have been attributed to its ability to regulate cell metabolism.⁴⁴⁴ Pterostilbene is a naturally occurring resveratrol analog that has shown similar properties in preclinical research.⁴⁴⁵ Resveratrol inhibits pro-inflammatory eicosanoid production and NF-kappaB signaling, downregulating inflammasome and cytokine signaling.^444,446 It also appears to improve gut microbiome composition and gut barrier function.^444,447

A meta-analysis that included findings from 35 randomized controlled trials with a total of 1,128 participants found resveratrol reduced hs-CRP and CRP levels, and was more effective when used for 10 weeks or longer and at daily doses of 500 mg or more.⁴⁴⁸ Furthermore, an umbrella meta-analysis that pooled data from 19 meta-analyses involving a total of 4,088 participants found resveratrol lowered CRP and TNF-α levels but had no significant effect on IL-6 levels. The analysis also showed treatment with at least 500 mg of resveratrol daily for at least 12 weeks led to weight loss, which may have been related to reduced inflammatory signaling.⁴⁴⁹

Resveratrol may have anti-inflammatory effects in people with specific chronic inflammatory disorders. A meta-analysis that pooled findings from six randomized controlled trials in subjects with cardiovascular disease found treatment with resveratrol lowered levels of CRP and TNF-α, but not IL-6, and only when used at doses higher than 15 mg daily.⁴⁵⁰ Similarly, meta-analyses of randomized controlled trials have shown resveratrol reduced hs-CRP and TNF-α (but not IL-6) levels in patients with metabolic-associated fatty liver disease (MAFLD)⁴⁵¹ and those with metabolic syndrome.⁴⁵² Another meta-analysis combined findings from six randomized controlled trials involving a total of 533 subjects with type 2 diabetes and found resveratrol, at doses of 40–1,000 mg daily, reduced CRP levels but did not change IL-6 or TNF-α levels.⁴⁵³

Curcumin

Reported dosage: 250–3,000 mg curcumin daily

Curcumin is a potent antioxidant carotenoid found in turmeric. Its anti-inflammatory effects are well established and attributable in part to its ability to suppress NF-kappaB, thereby downregulating inflammatory cytokine signaling.⁴⁵⁴ Numerous clinical trials have indicated curcumin may be helpful in treating a variety of chronic inflammatory disorders, particularly metabolic diseases, osteoarthritis, and rheumatic conditions.⁴⁵⁵

A systematic review and meta-analysis that included data from 66 randomized controlled trials found curcumin decreased levels of most biomarkers of inflammation; specifically, curcumin lowered CRP, IL-6, and TNF-α, but not IL-1β levels. In general, trials that used more absorbable forms of curcumin used lower doses (80–120 mg per day), whereas most trials that used common curcumin extracts used higher doses (250–3,000 mg per day).⁴⁵⁶ In a meta-analysis of 20 randomized controlled trials involving 1,394 subjects with metabolic syndrome, nano-curcumin (a form developed for increased absorbability), at doses of 80–180 mg daily, was found to decrease levels of hs-CRP, IL-6, and TNF-α. Notably, the analysis also found nano-curcumin improved markers of cardiovascular and metabolic health.⁴⁵⁷ Curcumin was also found to reduce inflammatory biomarker levels in two meta-analyses of trials in chronic kidney disease patients, including those requiring hemodialysis.^458,459 A meta-analysis of six randomized controlled trials in patients with rheumatoid arthritis and ulcerative colitis showed curcumin, at doses of 250–1,500 mg per day for 8–12 weeks, reduced CRP levels.⁴⁶⁰ A randomized placebo-controlled trial in 70 patients with SLE found 1,000 mg of curcumin daily for 10 weeks reduced levels of IL-6, but not other inflammatory markers.⁴⁶¹

Omega-3 PUFAs

Reported dosage: 900–2,000 mg daily

Fish oil is a rich source of the omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These fatty acids can be incorporated into cell membranes and used to synthesize anti-inflammatory eicosanoids (prostaglandins and leukotrienes) as well as SPMs, which have a vital role in resolving inflammatory reactions.^462,463 Omega-3 PUFAs also exert anti-inflammatory effects by modulating the gut microbiome.⁴⁶² EPA and DHA supplements have been shown to improve outcomes in clinical trials involving patients with a wide range of inflammatory disorders, such as coronary artery disease, type 2 diabetes, obesity, metabolic-associated liver disease, Alzheimer disease, SLE, and rheumatoid arthritis.^464-466

Higher fish oil or omega-3 PUFA intake has been associated with lower inflammatory marker levels, in observational research.⁴⁶⁷ One study in 402 subjects found a higher omega-6:omega-3 ratio was associated with higher CRP levels in those with chronic pain.⁴⁶⁸ Another study involving 101 subjects with advanced coronary artery disease prior to surgery found higher intake of omega-3 PUFAs, and a lower ratio of omega-6:omega-3 PUFAs, was correlated with a lower NLR, as well as a lower systemic inflammatory index value (a number calculated by multiplying the numbers of neutrophils by platelets and dividing by lymphocytes).⁴⁶⁹ In 105 men who had already undergone surgery for coronary artery disease and completed a dietary intake questionnaire, higher omega-3 PUFA intake was linked to lower PLR, but only those with a lower omega-6:omega-3 ratio had reduced CRP levels.⁴⁷⁰ Large observational studies have also reported correlations between higher omega-3 intake and lower levels of traditional inflammatory biomarkers.^168,169 In one study that included 2,920 Greek men and women without known cardiovascular disease, participants who consumed over 300 grams (about 10 oz.) of fish per week had, on average, 33% lower CRP, 33% lower IL-6, and 21% lower TNF-α levels than participants who did not consume fish.¹⁷⁰ In a sample of 5,677 men and women without cardiovascular disease participating in the Multi-Ethnic Study of Atherosclerosis (MESA), higher EPA and DHA intake was associated with reduced plasma concentrations of multiple inflammatory markers, including hs-CRP, IL-6, and soluble TNFR1.¹⁷¹

Numerous randomized controlled trials and multiple meta-analyses have shown omega-3 fatty acid supplementation can improve inflammatory marker levels. For example, in a randomized controlled trial in 60 patients receiving standard treatment following a heart attack, adding 2 grams of omega-3 PUFAs per day to treatment for 30 days lowered hs-CRP levels compared with placebo.⁴⁷⁵ A large meta-analysis of 48 randomized controlled trials including 8,489 subjects with metabolic syndrome found omega-3 PUFA supplementation led to decreased IL-1, IL-6, CRP, and TNF-α levels and reduced some cardiovascular risk factors. The analysis also showed the effects were stronger when the dose was 2 grams or less and increased over time with ongoing use.⁴⁷⁶ A meta-analysis of 13 clinical trials involving 853 patients with coronary artery disease found supplementing with omega-3 fatty acids reduced hs-CRP, IL-6, and TNF-α levels and improved blood vessel function.⁴⁷⁷ Another meta-analysis of 10 randomized controlled trials investigating the effects of 0.9–8 grams of fish oil per day in heart failure patients found supplementing with omega-3 fatty acids, particularly at doses ≤ 2 grams per day, reduced IL-6 and TNF-α levels, but not CRP or IL-1 levels.⁴⁷⁸

Vitamin D

Reported dosage: 12.5–100 mcg (500–4,000 IU) daily

Vitamin D appears to exert anti-inflammatory activity by lowering inflammatory cytokine levels, reducing pro-inflammatory prostaglandins, and inhibiting activation of NF-kappaB.⁴⁹¹ Multiple meta-analyses of randomized controlled trials have shown vitamin D supplementation can reduce CRP and TNF-α levels in various populations.^492,493 Vitamin D was found to significantly reduce hs-CRP and TNF-α levels and marginally lower IL-6 levels in a meta-analysis of randomized controlled trials involving type 2 diabetes patients. Some trials in this analysis used periodic or single high doses of vitamin D, whereas others used lower daily doses. In general, trials in which inflammatory markers decreased used dosing schemes averaging 12.5–100 mcg (500–4,000 IU) per day.⁴⁹⁴ In a meta-analysis that included eight trials in 592 patients with cancer or precancerous lesions, vitamin D was found to decrease TNF-α levels. It also reduced CRP and IL-6 levels, although these changes were not statistically significant. All but one of the studies in this analysis used doses averaging 20–100 mcg (800–4,000 IU) daily.⁴⁹⁵ One meta-analysis that pooled findings from six randomized controlled trials involving 758 postmenopausal women found, at doses averaging 10–70 mcg (400–2,800 IU) daily, vitamin D reduced CRP levels. The analysis also showed the effect was strongest in trials lasting three months or longer, trials that used ≤ 25 mcg (1,000 IU) of vitamin D per day, and trials that used vitamin D3.⁴⁹⁶ A meta-analysis of 11 trials in a total of 3,049 patients with rheumatoid arthritis found vitamin D at doses higher than 100 mcg (4,000 IU) daily had a more significant CRP-lowering effect than lower doses.⁴⁹⁷

Vitamin E

Reported dosage: 400–1,800 IU alpha-tocopherol or 250 mg tocotrienols daily

Vitamin E is a fat-soluble antioxidant that protects lipids throughout the body from free radical damage and reduces inflammation.⁴⁹⁹ A meta-analysis that included findings from 26 randomized controlled trials with a total of 2,102 participants found vitamin E reduced CRP levels. Vitamin E was also found to lower IL-6 levels when alpha-tocopherol form of vitamin E was used and in trials involving subjects with insulin resistance. It also reduced TNF-α levels when used at doses ≥ 700 mg (approximately 1,000–1,500 IU, depending on the type of vitamin E) per day. Most of the trials in the analysis used doses of 400–1,800 IU.⁵⁰⁰ In a meta-analysis of seven randomized placebo-controlled trials with a total of 504 participants, supplementation with vitamin E plus omega-3 fatty acids reduced hs-CRP levels. Along with 400 IU of vitamin E, treatment groups in five trials received 400 mg of alpha-linolenic acid from flaxseed oil and in the other two trials they received 1,000 or 4,000 mg of omega-3 fats from fish oil.⁵⁰¹ A systematic review found the tocotrienol fraction of vitamin E, at 250 mg daily, reduced markers of inflammation; specifically, CRP and IL-1 levels were reduced with tocotrienol supplementation.⁵⁰²

Vitamin C

Reported dosage: 400–2,000 mg oral vitamin C daily

Vitamin C is an antioxidant nutrient with an important role in immune regulation and tissue repair. Insufficient and deficient vitamin C levels have been linked to elevated hs-CRP levels in observational studies.^503-506 One study compared outcomes in 42 patients hospitalized with sepsis (systemic infection) who received standard care plus intravenous vitamin C (3 grams once daily for three days) to 42 similar patients who received standard care alone. Those who received vitamin C had lower levels of hs-CRP and TNF-α, less heart muscle damage, and lower risk of death (9.52% vs. 29.27%).⁵⁰⁷

Multiple clinical trials have indicated vitamin C can reduce inflammatory marker levels. A meta-analysis of 12 studies with a total of 893 participants found that vitamin C supplementation reduced CRP levels. A detailed analysis found the effect was stronger in clinical trials that measured hs-CRP, in subjects with baseline CRP levels of ≥3 mg/L, in subjects aged <60 years, and in trials that used intravenous vitamin C.⁵⁰⁸ In a randomized, controlled, crossover trial, 58 healthy young adults exposed to air pollution in a large Chinese city received 2,000 mg vitamin C daily and placebo, each for one week, in random order. Compared with placebo, vitamin C reduced CRP levels by 34.01%, TNF-α levels by 17.30%, and IL-6 levels by 19.47%.⁵⁰⁹ A small randomized placebo-controlled trial in 24 elderly women engaged in an exercise training program found 1,000 mg of vitamin C daily for six weeks lowered IL-6 gene expression levels yet increased expression of the anti-inflammatory cytokine IL-10 compared with placebo, although these effects were not statistically significant.⁵¹⁰ A meta-analysis of six randomized controlled trials with 111 participants found vitamin C supplementation, at doses ranging from 400–1,500 mg daily, mitigated an acute rise in IL-6 levels brought on by a single bout of exercise; however, pooled findings from three randomized controlled trials with a total of 70 participants did not find a significant effect on CRP levels.⁵¹¹

Zinc

Reported dosage: 15–100 mg elemental zinc daily

Zinc is a critical nutrient for balanced immune function, and a growing body of research indicates that zinc has a role in downregulating NF-kappaB signaling.⁵¹² Low zinc status has been associated with high CRP levels in multiple observational studies.^513,514 One report examined the effect of zinc supplementation on immune parameters (including IL-6, CRP, and hs-CRP levels) by performing a series of meta-analyses on data from 35 randomized controlled trials involving 1,995 subjects. The analyses found zinc lowered CRP, hs-CRP, and TNF-α levels. It also showed zinc supplementation lowered IL-6 levels, but only when used at doses of 50 mg per day or less. Finally, zinc reduced circulating neutrophils without affecting numbers of lymphocytes, indicating a reduction in the NLR. Although the trials included in this report used a variety of forms and doses of zinc, most used doses providing 15–100 mg of elemental zinc per day.⁵¹⁵ Two other meta-analyses that included findings from randomized controlled trials involving subjects with type 2 diabetes showed zinc supplementation reduced CRP levels and improved other markers of cardiometabolic health.^516,517 Another meta-analysis included 75 randomized controlled trials: by pooling findings from 24 trials, the analysis found zinc supplementation reduced CRP levels. Furthermore, pooled findings from 15 trials showed zinc decreased levels of IL-6 (in trials using 30 mg zinc or more) and TNF-α (in trials lasting up to eight weeks). Meta-analysis of other trials showed zinc also improved some markers of oxidative stress and cardiovascular risk.⁵¹⁸

Carotenoids

Reported dosage: 4–30 mg lycopene, 10–20 mg lutein, 5 mg zeaxanthin, 4–20 mg astaxanthin, or 30 mg crocin daily

Carotenoids are a family of lipid-soluble phytonutrients that provide pigmentation to plants and have important antioxidant, anti-inflammatory, and anti-aging properties.⁵¹⁹ Carotenoids can suppress NF-kappaB pathways, reducing pro-inflammatory cytokine levels. They also support intestinal health and function and improve microbiome balance, which may further decrease inflammation.^520,521 Some of the most studied dietary carotenoids are^519,522:

• Beta-carotene, mainly from yellow and orange vegetables
• Lycopene, mainly from tomatoes
• Lutein, mainly from egg yolk and green leafy vegetables
• Astaxanthin, mainly from pink to red seafood (salmon and crustaceans) and algae extracts

A large systematic review included findings from 17 correlational studies, 12 clinical trials involving dietary interventions, and nine clinical trials involving supplements. The review determined carotenoids, in general, decreased levels of inflammatory biomarkers and reduced cardiovascular risk, and dietary sources may have been more effective than supplements.⁵²² A meta-analysis that pooled findings from 26 randomized controlled trials found carotenoid supplements led to reduced levels of CRP and IL-6, but not TNF-α; however, a more detailed analysis found only lycopene reduced IL-6 levels, whereas lutein, zeaxanthin, astaxanthin, and cryptoxanthin reduced CRP levels.⁵²³ Dosages of carotenoids used in the studies summarized in the two meta analyses just described were 5–30 mg/d for lycopene, 10–20 mg/d for lutein, 5 mg/d of zeaxanthin, 15–22 mg/d of beta-carotene, and about 16 mg/d of alpha-carotene. Another meta-analysis included 17 controlled trials investigating the effects of lycopene on cardiovascular disease markers. The analysis showed lycopene, at doses ranging from 4–30 mg per day, lowered levels of IL-6, but not CRP, and improved several other cardiovascular risk factors.⁵²⁴ A separate meta-analysis that included data from 12 randomized controlled trials showed that astaxanthin, another carotenoid, reduced IL-6 levels in people with type 2 diabetes. This analysis also showed that astaxanthin reduced some markers of oxidative stress, such as malondialdehyde, with this effect more pronounced in those with type 2 diabetes. In trial trials included in the meta-analysis, astaxanthin dosage ranged from 4 mg to 20 mg daily and the trial duration ranged from four weeks to 12 months.⁵²⁵

Crocin is a carotenoid from saffron (Crocus sativus) that has demonstrated positive health effects related to its anti-inflammatory and free radical-scavenging properties. A meta-analysis that included data from 13 randomized controlled trials determined crocin was effective for lowering CRP, IL-6, and TNF-α levels, and the effects were stronger when doses of at least 30 mg per day were used for at least 12 weeks.⁵²⁶ For example, in randomized controlled trials, 15 mg of crocin twice daily for 12 weeks resulted in lower IL-6 and TNF-α levels compared with placebo in patients with chronic obstructive pulmonary disease (COPD) and in women with polycystic ovary syndrome (PCOS).^527,528 The same crocin intervention was found to reduce hs-CRP and TNF-α levels, as well as NF-kappaB activity, in a randomized placebo-controlled trial in 50 participants with type 2 diabetes.⁵²⁹

Polyphenols

Reported dosage: Greater than 450 mg cocoa flavanols or 300–1,500 mg green tea extract daily

Polyphenols are a large family of plant compounds (including flavonoids) that are well-known for their free radical-scavenging and anti-inflammatory properties. Tea, coffee, berries, and other fruits are among the most widely consumed sources of polyphenols; and diets rich in these foods have been associated with lower levels of CRP, IL-6, and IL-8.^530-532 Preclinical research has shown dietary polyphenols have anti-inflammatory actions: they suppress NF-kappaB, thereby reducing inflammatory cytokine signaling; they inhibit the cyclooxygenase enzymes COX1 and COX 2, thereby limiting synthesis of pro-inflammatory eicosanoids; they decrease migration of white blood cells; and they modulate gut microbiome and improve gut barrier function.^533,534

Higher intake of dietary polyphenols was linked to lower levels of CRP and fibrinogen in an observational study that used data from over 9,000 adults.⁵³⁵ Drinking a polyphenol-rich tea made from yerba mate (Ilex paraguariensis) for eight days lowered IL-6 and TNF-α levels compared with eight days of drinking water in a crossover trial involving nine men.⁵³⁶

Cocoa is a source of polyphenols known as flavanols. A meta-analysis of data from 33 controlled trials indicated dark chocolate or cocoa interventions, such as dark chocolate, cocoa powder, and cocoa beverages, reduced CRP levels when the amount of cocoa flavanols exceeded 450 mg per day, particularly in non-healthy subjects.⁵³⁷

Green tea is high in polyphenols called catechins. A randomized placebo-controlled trial in 28 postmenopausal women with overweight or mild obesity found supplementing with 150 mg of a polyphenol-rich green tea extract twice daily for 60 days lowered CRP levels and improved some markers of metabolic health.⁵³⁸ One meta-analysis included five randomized controlled trials that investigated changes in CRP levels in 383 subjects with type 2 diabetes; the analysis found CRP levels dropped 5.51 mg/dL more in those treated with green tea, at daily doses of 500–1,500 mg, than in those who served as controls.⁵³⁹ A separate meta-analysis of findings from 11 randomized controlled trials found epigallocatechin-gallate (EGCG), the main active polyphenol in green tea, had no effect on CRP levels, regardless of dose, duration, or participant health status.⁵⁴⁰

Boswellia

Reported dosage: 100–1,000 mg Boswellia extract or about 133–800 mg boswellic acids daily

Boswellia (Boswellia serrata), also known as frankincense, is a traditional anti-arthritis herb used in Ayurvedic medicine. Boswellic acid found in the gum resin has been found to modulate activity of lipoxygenase enzymes, shifting fatty acid metabolism in favor of less-inflammatory eicosanoids and anti-inflammatory SPMs.⁵⁴¹

In a randomized controlled trial that included 70 subjects with osteoarthritis of the knee, 100 mg daily of a Boswellia gum resin extract for 30 days reduced hs-CRP and TNF-α levels and decreased joint stiffness and pain.⁵⁴² A randomized placebo-controlled trial in 47 patients hospitalized with a severe, acute, viral respiratory infection found treatment with 333 mg of Boswellia extract (standardized to provide 133 mg of boswellic acids) three times daily reduced multiple markers of inflammation, including NLR and CRP, IL-6, and TNF-α levels. It also led to greater symptom improvement and shorter hospitalization compared with placebo.⁵⁴³ In a randomized controlled trial that compared 800 mg of boswellic acid three times daily to placebo in 80 ischemic stroke patients, boswellic acid-treated participants had decreased levels of TNF-α, IL-1β, IL-6, and IL-8, as well as prostaglandin E2, after seven days and greater neurological recovery after 30 days.⁵⁴⁴

Boswellia is often combined with other anti-inflammatory nutrients. In a randomized controlled trial in 90 subjects with chronic low back pain, 300 mg of combined Boswellia plus curcumin daily for 90 days reduced hs-CRP, IL-6, and TNF-α levels, alleviated pain and disability, and improved quality of life scores compared with placebo.⁵⁴⁵ A randomized placebo-controlled trial that included 62 participants with knee osteoarthritis found supplementing with 300 mg of Boswellia extract plus 250 mg of celery (Apium graveolens) seed extract twice daily for 90 days decreased levels of hs-CRP, IL-1, IL-6, IL-7, and TNF-α; reduced pain, stiffness, and swelling; and reduced biomarkers of cartilage degeneration.⁵⁴⁶

Protein Supplements

Reported dosage: 30–87 grams of whey protein or 15–40 grams soy protein daily

Protein supplements contain bioactive peptides that, when released, may reduce markers of inflammation.⁵⁴⁷ One meta-analysis included 31 randomized controlled trials investigating the effects of protein supplements (18 using whey protein and 13 using soy protein) on inflammatory marker levels in elderly subjects. Pooled analysis of results from trials that used whey protein found 30 grams or more of whey protein per day reduced IL-6 levels, particularly in those with sarcopenia and pre-frailty. Whey protein was also found to reduce CRP levels but only in subjects without obesity. The analysis also showed soy protein, at doses of 15–40 grams daily, reduced TNF-α levels, and the effect was enhanced when soy isoflavones were present in the soy supplement.⁵⁴⁸ Whey protein dosages in the included studies ranged from 15 to 87 grams per day, and the reported soy protein dosages ranged from 15 to 52 grams per day. On the other hand, a meta-analysis that included 11 randomized controlled trials found whey protein did not affect levels of IL-6 or TNF-α, regardless of health status.⁵⁴⁹

Magnesium

Reported dosage: 250–500 mg daily

Higher magnesium intake and blood levels have been associated with lower hs-CRP levels in multiple observational studies.^550-552 A study in 5,775 subjects, aged 40–73 years, found higher magnesium intake was correlated with lower hs-CRP and GlycA levels, as well as a lower number of leukocytes (a type of white blood cell, mainly consisting of neutrophils).⁵⁵³ Another study found a link between higher magnesium intake and lower IL-6 levels in participants with a gene variant known to affect magnesium metabolism.⁵⁵⁴

Clinical trials investigating magnesium’s effect on markers of inflammation have yielded mixed results. One placebo-controlled trial in 60 coronary artery disease patients found 300 mg of magnesium sulfate daily for three months lowered serum levels, as well as gene expression levels, of the pro-inflammatory cytokines IL-18 and TNF-α.⁵⁵⁵ A meta-analysis of 17 randomized controlled trials with a combined total of 889 participants found magnesium supplementation, in doses ranging from 250–500 mg per day, decreased CRP levels compared with placebo, but had no effect on IL-6 or TNF-α. Some trials in the analysis found magnesium lowered IL-1 and fibrinogen levels, but these effects were not measured in enough trials to be included in the meta-analysis.⁵⁵⁶ However, another meta-analysis of 18 trials with 927 participants found no reduction in CRP, IL-6, or TNF-α levels with magnesium supplementation.⁵⁵⁷ People with existing inflammation may benefit more from magnesium treatment than those without inflammation. A meta-analysis that included 11 randomized controlled trials found that whereas magnesium did not lower CRP levels in the overall analysis, it did lower CRP levels in a subset of participants whose baseline CRP levels were ≥3.0 mg/dL.⁵⁵⁸

Selenium

Reported dosage: 150–200 mcg daily

Selenium is a vital nutrient for reduction–oxidation balance, and some evidence suggests selenium may help regulate inflammatory activity in the immune system.^559,560 Selenium levels have been reported to be lower in patients with autoimmune and cardiovascular diseases, compared to the overall population.⁵⁶¹ An observational study that included 606 elderly subjects with cardiovascular disease and 858 healthy elderly individuals found selenium deficiency was correlated with increased CRP levels and neutrophil-to-lymphocyte ratios, as well as increased likelihood of cardiovascular disease.⁵⁶² A meta-analysis that included four randomized controlled trials investigating CRP changes in coronary heart disease patients found treatment with selenium, at doses of 150–500 mcg daily, reduced CRP levels, though it did not affect mortality.⁵⁶³ Another meta-analysis that included 13 randomized controlled trials also found selenium supplementation was effective for reducing CRP levels. Most of the included studies used 200 mcg of selenium; however, the range of doses used was 50–500 mcg per day.⁵⁶⁴

The effect of intravenous selenium on markers of inflammation appears to be somewhat different than with oral selenium supplementation. A meta-analysis that pooled findings from 24 randomized controlled trials found intravenous selenium administration reduced CRP and IL-6 levels but increased TNF-α levels, whereas oral selenium supplementation only had an effect on IL-6.⁵⁶⁵

N-acetylcysteine

Reported dosage: 400–2,000 mg daily

N-acetylcysteine (NAC), a form of the amino acid cysteine, can be used to synthesize glutathione. Glutathione is a major biological oxidative stress modulator and has been shown to regulate immune cell activity and inhibit release of pro-inflammatory cytokines.⁵⁶⁶

In a controlled study involving 32 patients with acute myocardial infarction (heart attack), those who received standard therapies plus 600 mg of NAC every eight hours for three days had reduced galectin-3 and hs-CRP levels compared with those who receive standard therapies alone.⁵⁶⁷ One meta-analysis that pooled findings from 24 randomized controlled trials with a total of 1,057 participants found treatment with NAC, at doses of 400–2,000 mg daily for up to 80 weeks, reduced CRP and IL-6 levels but did not affect other markers of inflammation.⁵⁶⁸ A meta-analysis of 28 randomized controlled trials found NAC significantly improved TNF-α, IL-6, IL-8, and homocysteine levels, though not CRP.⁵⁶⁹ A systematic review and meta-analysis of 20 randomized controlled trials found treatment with NAC before exercise decreased post-exercise levels of IL-6, but not TNF-α, and raised glutathione levels.⁵⁶⁶

Bromelain

Reported dosage: 90–500 mg daily

Typically derived from pineapple stem, bromelain—a mixture of proteolytic enzymes—has demonstrated a variety of anti-inflammatory properties in preclinical research.^272,571 Bromelain has been shown to reduce NF-kappaB activation, pro-inflammatory cytokine signaling, and inflammatory immune cell activity. It also reduces COX-2 enzyme expression, decreasing the synthesis of prostaglandins,^572,573 and modulates the inflammatory response through its effects on fibrin and fibrinogen.^272,572

Human trials of bromelain for inflammatory conditions have yielded promising results.²⁷³ Bromelain has been reported to reduce swelling and relieve pain after dental surgery and improve symptoms in subjects with knee pain and arthritis.^{274,275,277,576} In addition, a combination of bromelain plus trypsin (an enzyme that breaks down proteins) and rutoside (a flavonoid) reduced pain and inflammation comparably with a non-steroidal anti-inflammatory drug (NSAID) (diclofenac), and also enhanced the effectiveness of this drug.^274,276

A systematic review examined the effect of bromelain on levels of inflammatory biomarkers using findings from seven randomized controlled trials. Although the trials had substantial differences in forms of bromelain used, biomarkers measured, and participant populations, bromelain appeared generally to have beneficial effects on markers of inflammation including reductions in CRP, IL-6, IL-5, IL-12, and PGE2 levels. Trials in this review that found reductions in inflammatory marker levels used doses of 90–500 mg bromelain daily, sometimes in divided doses and/or combined with other nutrients.⁵⁸⁰

Sesame

Reported dosage: 200 mg of sesamin or 40 grams of ground sesame seeds daily

Sesame oil and its lignans (sesamin, sesamolin, sesaminol, and sesamol) have demonstrated anti-inflammatory and immune-regulating effects in numerous preclinical studies. Actions attributed to sesame oil constituents include inhibiting cyclooxygenase (COX)-2 enzyme, thereby decreasing production of inflammatory eicosanoids, and downregulating NF-kappaB, thereby suppressing production of pro-inflammatory cytokines.^332,589,590 In a randomized controlled trial in 44 women with rheumatoid arthritis, 200 mg of sesamin daily for six weeks lowered levels of hs-CRP, TNF-α, and COX-2, but not IL-1β or IL-6, and decreased joint tenderness and pain compared with placebo.⁵⁹¹ Another randomized controlled trial in 50 subjects with knee osteoarthritis found 40 grams of ground sesame seeds per day for two months reduced levels of IL-6, but not hs-CRP.⁵⁹² However, in a randomized crossover trial in 30 adults with overweight or obesity, 25 grams of sesame daily for five weeks had a similar effect to placebo on levels of CRP, IL-6, and TNF-α.⁵⁹³

Modified Citrus Pectin

Reported dosage: 20 grams daily

Citrus pectin is a dietary fiber and a large complex molecule that is not digested or absorbed by the human digestive system. Modified citrus pectin (MCP) is an enzymatically processed form of pectin made up of smaller molecules that are absorbed into circulation.⁵⁹⁴ Pectin and MCP bind to and inactivate galectin-3, a binding protein involved in inflammation, fibrosis, and cancer metastasis.⁵⁹⁵ MCP has also been shown to downregulate NF-kappaB and reduce expression of pro-inflammatory cytokines.⁵⁹⁶ Furthermore, MCP can be metabolized by intestinal bacteria, resulting in products that may also help regulate inflammation.⁵⁹⁷ The anti-inflammatory effects of MCP are thought to underlie the positive health effects it has demonstrated in preclinical research, such as decreasing cardiovascular inflammation, protecting against cardiac fibrosis, reducing atherosclerotic plaques, and enhancing cartilage healing.^598-602 In addition, a growing body of evidence suggests it may improve certain outcomes in cancer patients.⁵⁹⁴

In a pilot clinical trial in 29 healthy adults, 20 grams of modified citrus pectin daily for four weeks reduced levels of IL-1β, IL-6, and TNF-α; raised levels of anti-inflammatory IL-10; and reduced anxiety scores significantly more than placebo.⁶⁰³

Mitochondrial Support

Reactive oxygen species generated during mitochondrial respiration contribute to inflammation, as outlined previously in the protocol. Aging individuals are especially susceptible to mitochondria-related oxidative stress since mitochondria become increasingly dysfunctional with age.^604,605 Taking steps to support mitochondrial integrity and efficiency can help alleviate some of the systemic oxidative and inflammatory burden caused by poorly functioning mitochondria.⁶⁰⁶ Two nutrients, coenzyme Q10 and pyrroloquinoline quinone, are powerful mitochondrial protectants, and studies support an anti-inflammatory role for these compounds.^607,608

Pyrroloquinoline quinone

Reported dosage: 300 mcg per kg body weight or approximately 20 mg daily

Pyrroloquinoline quinone (PQQ) is a cofactor for enzymes critically important for cellular energy homeostasis and redox balance. Several studies have shown that PQQ promotes new mitochondria formation, supports mitochondrial function, and reduces oxidative stress.⁶⁰⁸ Preclinical research has suggested PQQ can reduce joint inflammation; suppress release of IL-1β, IL-6, and TNF-α by injured joint cells; and protect mitochondria in cartilage cells from cytokine-induced damage.^609,610 In 10 healthy adults, 300 mcg per kg body weight of PQQ daily for three days increased antioxidant status, decreased CRP and IL-6 levels, and raised markers of mitochondrial function.⁶¹¹ In addition, randomized controlled trials have found 20–21.5 mg of PQQ daily for 6–12 weeks increased brain blood flow, brain oxygenation, brain cell activity, and cognitive performance in older individuals, and improved the mitochondrial response to endurance training in healthy men.^612-615

Coenzyme Q10

Reported dosage: 100–400 mg daily

Coenzyme Q10 (CoQ10) is found in lipid cell membranes, especially in mitochondrial membranes, where it is needed for ATP production. It is also a free radical scavenger that protects lipids from oxidative damage and participates in lipid metabolism.⁶⁰⁷ Studies have shown CoQ10 levels are low in individuals with a broad range of age-related and inflammatory conditions, including cardiovascular, metabolic, neurological, and kidney diseases; and lower levels are associated with increased mortality risk.^616,617 Furthermore, supplementation has been shown to be helpful in these and other inflammatory conditions, including rheumatic diseases.^616,618

CoQ10 supplementation has been found to reduce levels of inflammatory biomarkers in numerous clinical trials. One systematic review and meta-analysis that examined data from 31 randomized controlled trials involving a total of 1,517 participants concluded that CoQ10, at daily doses of 300–400 mg, was effective for reducing levels of CRP, IL-6, and TNF-α.⁶¹⁹ A meta-analysis that pooled data from six randomized placebo-controlled trials involving 318 participants with metabolic syndrome found 100–200 mg of CoQ10 daily increased levels of adiponectin (an anti-inflammatory cytokine produced by fat cells), improved oxidative stress indicators, and lowered levels of inflammatory biomarkers.⁶²⁰ On the other hand, a meta-analysis that included 13 randomized controlled trials involving subjects with coronary artery disease found CoQ10 did not lower levels of CRP, IL-6, or TNF-α, though it did reduce oxidative stress.⁶²¹

Counteracting Proinflammatory Glycation Reactions

Interactions between advanced glycation end products (AGEs) and their receptor (RAGE) play a key role in promoting acute and chronic inflammation by activating inflammatory signaling pathways such as NF-kappaB and stimulating the release of pro-inflammatory cytokines.^622,623 Fortunately, in addition to dietary measures for controlling blood glucose concentrations and avoiding high-AGE foods, some natural compounds inhibit glycation and may help rein in the inflammatory cascade.⁶²²

Benfotiamine

Reported dosage: 100–600 mg daily along with other B vitamins

Benfotiamine is a synthetic fat-soluble derivative of vitamin B1 (thiamine). Thiamine and benfotiamine activate an enzyme involved in the breakdown of AGE precursors, thereby decreasing AGE production, AGE/RAGE interactions, and related inflammatory signaling.⁶²⁴ It has demonstrated potent antioxidant and anti-inflammatory properties and has been shown to help prevent diabetes complications related to inflammation in animal studies.^625,626 Moreover, laboratory experiments have indicated benfotiamine may regulate inflammation by modulating COX and LOX enzyme activity.⁶²⁷

In a randomized controlled trial in 70 patients with mild cognitive impairment or mild dementia related to Alzheimer disease, 300 mg of benfotiamine twice daily for 12 months slowed the progression of cognitive decline and the rise in circulating AGE levels compared with placebo.⁶²⁸ In a randomized placebo-controlled trial, 30 subjects with osteoarthritis were given a supplement providing 50 mg of benfotiamine, 50 mg of pyridoxamine (vitamin B6), and 500 mcg of methylcobalamin (vitamin B12) or placebo to take three times daily for 24 weeks. The supplement group had reduced arthritis pain and disability scores, decreased AGE levels, and lower CRP levels compared with the placebo group at the end of the trial.⁶²⁹ An uncontrolled trial involving 24 rheumatoid arthritis patients found the same supplement, taken twice daily for 12 weeks, improved a measure of blood vessel function called flow-mediated vasodilation, decreased CRP levels, and lowered disease activity scores.⁶³⁰ In a randomized controlled trial, 165 subjects with diabetic neuropathy were randomized to receive 300 or 600 mg of benfotiamine per day or placebo for six weeks. Neuropathy symptom scores were reduced in those taking benfotiamine, and the effect was stronger in those taking the higher dose.²²⁰

However, not all clinical trials have found benfotiamine to improve inflammation in individuals with type 1 or type 2 diabetes. In one randomized placebo-controlled trial in patients with type 1 diabetes, 300 mg of benfotiamine daily for 24 months did not affect inflammatory biomarker levels or nerve function.⁶³² Another randomized placebo-controlled trial in 39 type 2 diabetes patients with evidence of kidney damage found benfotiamine, at 300 mg three times daily for 12 weeks, did not reduce levels of AGEs or inflammatory biomarkers and did not improve vascular function.⁶³³

Carnosine

Reported dosage: 500–2,000 mg daily

Carnosine is a dipeptide made from the amino acids beta-alanine and histidine and found mainly in meat. Carnosine has been shown to scavenge free radicals, downregulate inflammatory signaling, and inhibit glycation.^634,635 A meta-analysis of nine randomized controlled trials with a total of 350 participants found supplementing with carnosine, at doses ranging from 500 to 2,000 mg per day, or its amino acid precursors reduced levels of CRP and TNF-α, but not IL-6.⁶³⁶ In one of the trials, 54 subjects with type 2 diabetes received 1,000 mg of carnosine or placebo daily for 12 weeks; carnosine was found to reduce AGE and TNF-α levels and improve markers of blood glucose control.⁶³⁷ However, in another trial in 41 patients with well-controlled type 2 diabetes or prediabetes, 2,000 mg of carnosine per day for 14 weeks did not reduce inflammatory biomarker levels relative to placebo.⁶³⁸ Carnosine is easily broken down in the digestive tract, which may account for mixed clinical results.⁶³⁹ Interestingly, supplementing with a carnosine metabolite called carcinine, at 60 mg daily for two months, was found to reduce AGE levels and improve markers of cardiometabolic health more than placebo in an observational study involving 100 volunteers with metabolic syndrome.⁶⁴⁰ Other research suggests topical carnosine may inhibit glycation reactions in the skin, reducing skin aging.⁶⁴¹

Hesperidin

Reported dosage: approximately 300–1,000 mg of hesperidin or 500–750 mL (~16–25 oz.) orange juice daily

Hesperidin and its metabolite hesperetin are flavonoids found mainly in citrus fruits, particularly their peels. These compounds are powerful free radical scavengers and have demonstrated anti-inflammatory, insulin-sensitizing, lipid-lowering, neuroprotective, and anti-aging activities.^642,643 Preclinical research has also indicated these compounds promote bone and cartilage repair through antioxidant and anti-inflammatory effects, which are partly due to downregulation of NF-kappaB.⁶⁴³ Furthermore, studies in animals suggest hesperidin can upregulate cellular metabolism by activating adenosine 5'-monophosphate protein kinase (AMPK), peroxisome proliferator-activated receptor (PPAR), and other signaling pathways.⁶⁴⁴

A growing body of research indicates hesperidin can promote insulin sensitivity and metabolic health by reducing chronic inflammation.^645,646 In a randomized controlled trial, 49 patients with metabolic syndrome received 500 mg of hesperidin or placebo twice daily for 12 weeks. Compared with placebo, hesperidin reduced TNF-α (but not hs-CRP), fasting blood glucose, and triglyceride levels, as well as systolic blood pressure.⁶⁴⁷ A meta-analysis that pooled results from six randomized controlled trials with 296 participants found hesperidin supplementation at doses of 292–600 mg daily reduced levels of vascular cell adhesion molecule (VCAM)-1, an adhesion molecule involved in the inflammatory response. Although hesperidin did not decrease CRP levels in the overall analysis, it was found to have a significant CRP-lowering effect in parallel (rather than crossover) trials and trials lasting longer than four weeks.⁶⁴⁸

Orange juice is an important dietary source of hesperidin and contains an array of related flavonoids in smaller concentrations. These compounds appear to contribute to orange juice’s immune-modulating and anti-inflammatory effects.⁶⁴⁹ A systematic review of 20 controlled clinical trials found 500–750 mL of orange juice daily lowered CRP, IL-6, and TNF-α levels, and the effects increased as the amount and duration of use increased.⁶⁵⁰