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Health Protocols

Inflammation (Chronic)

Risk Factors for Chronic Inflammation

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


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).


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


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


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

Excess Blood Glucose Fuels Inflammatory Fires

When glucose is properly utilized, our cells produce energy efficiently. As cellular sensitivity to insulin diminishes, excess glucose accumulates in our bloodstream. Like spilled gasoline, excess blood glucose creates a highly combustible environment from which oxidative and inflammatory fires chronically erupt.

Excess glucose not used for energy production converts to triglycerides that are either stored as unwanted body fat or accumulate in the blood where they contribute to the formation of atherosclerotic plaque.

As an aging human, you face a daily onslaught of excess glucose that poses a grave risk to your health and longevity. Surplus glucose relentlessly reacts with your body’s proteins, causing damaging glycation reactions while fueling the fires of chronic inflammation and inciting the production of destructive free radicals.69-71

Avert Glycation and Inflammation by Controlling Glucose Levels with Green Coffee Extract

Unroasted coffee beans, once purified and standardized, produce high levels of chlorogenic acid and other beneficial polyphenols that can suppress excess blood glucose levels. Human clinical trials support the role of chlorogenic acid-rich green coffee bean extract in promoting healthy blood sugar control and reducing disease risk.

Scientists have discovered that chlorogenic acid found abundantly in green coffee bean extract inhibits the enzyme glucose-6-phosphatase that triggers new glucose formation and glucose release by the liver.72,73 Glucose-6-phosphatase is involved in dangerous postprandial (after-meal) spikes in blood sugar.

In another significant mechanism, chlorogenic acid increases the signal protein for insulin receptors in liver cells.74 That has the effect of increasing insulin sensitivity, which in turn drives down blood sugar levels.

In a clinical trial, 56 healthy volunteers were challenged with an oral glucose tolerance test before and after a supplemental dose of green coffee extract. The oral glucose tolerance test is a standardized way of measuring a person's after-meal blood sugar response. In subjects not taking green coffee bean extract, the oral glucose tolerance test showed the expected rise of blood sugar to an average of 144 mg/dL after a 30-minute period. But in subjects who had taken 200 mg of the green coffee bean extract, that sugar spike was significantly reduced, to just 124 mg/dL—a 14% decrease.75 When a higher dose (400 mg) of green coffee bean extract was supplemented, there was an even greater average reduction in blood sugar—up to nearly 28% at one hour.

Ensuring fasting glucose levels stay between 70 and 85 mg/dL, and that two-hour post-meal glucose levels remain under 125 mg/dL, can help combat chronic inflammation.