Risk Factors for Chronic Inflammation
There are several risk factors which increase the likelihood of establishing and maintaining a low-level inflammatory response. These include:
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 (Singh et al. 2011). 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; see below).
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 (Trayhurn et al. 2005; Schrager et al. 2007). Visceral fat cells can produce three times the amount of IL-6 as fats cells elsewhere (Fried et al. 1998), and in overweight individuals, may be producing up to 35% of the total IL-6 in the body (Mohamed-Ali et al. 1997). Fat tissue can also be infiltrated by macrophages, which secrete pro-inflammatory cytokines. This accumulation of macrophages appears to be proportional to BMI, and appear to be a major cause of low-grade, systemic inflammation and insulin resistance in obese individuals (Ortega Martinez de Victoria et al. 2009, Weisberg et al. 2003).
Diet. A diet high in saturated fat is associated with higher pro-inflammatory markers, particularly in diabetic or overweight individuals (Nappo et al. 2002) (Peairs et al. 2011). This effect was absent in healthy individuals (Myhrstad et al. 2011, Poppitt et al. 2008, Payette et al. 2009). 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 (Mozaffarian et al. 2004) (Lopez-Garcia et al. 2005), but had no effect in others (Nielsen et al. 2011, Bendsen et al. 2011). The increases in markers of inflammation due to synthetic trans- fats may be more pronounced in individuals that are also overweight (Nielsen et al. 2011).
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 (Ahmadi 2011; González 2012). 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 (Gilliver 2010). 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-kb (Keller et al. 1996; Ray et al. 1997; Deshpande et al. 1997). 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) (Maggio et al. 2006, Khosla et al. 2002). Several studies have shown an increase in inflammatory IL-1β, IL-6, and TNF-α following surgical or natural menopause (reviewed in Gameiro et al. 2010) (Singh et al. 2011). 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 (reviewed in (Gilliver 2010). 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 hormone replacement therapy (Kane et al. 2008, Vural et al. 2006, Anderson et al. 2004).
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 (Arnson et al. 2010). Smoking also increases the risk of periodontal disease, an independent risk factor for increasing systemic inflammation (Lee et al. 2011).
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 (Vgontzas et al. 1997). 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 (Vgontzas et al. 1997). These elevations in cytokines were independent of body mass index or age (Vgontzas et al. 2000, Vgontzas et al. 2003), although persons with higher visceral body fat were more likely to have sleep disorders. (Trakada et al. 2007)
Other Inciting Factors
Periodontal disease can produce a systemic inflammatory response that may affect several other systems, such as the heart and kidneys (Slade et al. 2003, Pradeep et al. 2011). It is by this mechanism that periodontal disease is thought to be a risk factor for cardiovascular diseases (Vaishnava et al. 2011)
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 (Pervanidou et al. 2011).
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 (van Westerloo 2010). Preliminary data suggests that depressed nerve activity may be associated with exaggerated inflammatory responses seen in sepsis (Pontet et al. 2003). Smoking, itself a risk factor for inflammation, also decreases activity of the vagus nerve (Taylor et al. 2011).
Diseases Associated with Chronic Inflammation
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 (Singh et al. 2011, Emerging Risk Factors Collaboration et al. 2010).
Cancer. Several studies have established links between chronic low-level inflammation and many types of cancer, including lymphoma, prostate, ovarian, pancreatic, colorectal and lung (Aggarwal et al. 2006).(Kundu et al. 2008) 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 (Kundu et al. 2008, Balkwill 2009)
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 (Pickup et al. 2000, Nappo et al. 2002, Ortega Martinez de Victoria et al. 2009). Pro-inflammatory cytokines clearly decrease insulin sensitivity (Bastard et al. 2006).
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 (Hong et al. 2011). 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) (Glorieux et al. 2009). 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 (Cao 2011). 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 (Dantzer 2012). It is unclear whether inflammation leads to stress or vice versa, and there is data supporting both hypotheses (Gimeno et al. 2009) (Copeland et al. 2012).
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 (Singh et al. 2011). One study found that 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). (Yaffe et al. 2003). Inflammatory markers can be elevated before the onset of cognitive dysfunction, indicating their potential relevance as a prognostic tool in high-risk individuals (Singh et al. 2011).
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, sacropenia/cachexia/muscle wasting) (Kaser et al. 2011) (Jha et al. 2009) (Ferrucci et al. 2010, Kadetoff et al. 2011, Rolland et al. 2011). Again, whether inflammation incites these conditions or results from them is unclear, and requires further investigation.
Conventional Medicine Typically Overlooks Chronic Inflammation
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 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.