Chronic Inflammation in Disease Etiology: Implications for Health and Mortality

One of the most important medical discoveries of the last two decades has been that the immune system and inflammatory processes are involved not only in a few specific disorders but also in a wide variety of physical and mental health problems that dominate morbidity and mortality. current mortality, throughout the world.

Indeed, chronic inflammatory diseases have been recognized as the most important cause of death in the world today: More than 50% of all deaths are attributable to diseases related to inflammation, such as ischemic heart disease, stroke, cancer , diabetes mellitus, chronic kidney disease, nonalcoholic fatty liver disease, and autoimmune and neurodegenerative conditions.

There is growing evidence that the risk of developing chronic inflammation can be traced back to very early in life, and its effects are now known to persist throughout life and affect later life health and mortality risk.

Inflammation is an evolutionarily conserved process, characterized by the activation of immunological and non-immunological cells that protect the host from bacteria, viruses, toxins and infections, by eliminating pathogens and promoting tissue repair and recovery.

Depending on the degree and extent of the inflammatory response, whether systemic or local, metabolic and neuroendocrine , changes may occur to conserve metabolic energy and allocate more nutrients to the activated immune system.

Thus, the specific biobehavioral effects of inflammation include a constellation of energy-saving behaviors commonly known as “sickness behaviors” —sadness, anhedonia, fatigue, decreased libido and food intake, sleep disturbances, and social withdrawal. -behavioral, as well as high blood pressure, insulin resistance and dyslipidemia.

The changes may be critical for survival in times of physical injury and microbial threat.

The normal inflammatory response is characterized by the temporally restricted upregulation of inflammatory activity that occurs in the presence of a threat, which resolves when the threat has disappeared.

However, the presence of certain social, psychological, environmental and biological factors has been related to affecting the resolution of acute inflammation and, in turn, to promoting a state of low-grade, non-infectious chronic inflammation ( "sterile"), which is characterized by the activation of immunological components that are usually different from those involved during an acute immune response.

Changes in the inflammatory response from short to long duration can cause a collapse of immunological tolerance and lead to important alterations in all tissues and organs, as well as in normal cellular physiology, which can increase the risk of various non-communicable diseases, in both young people and older adults.

Chronic systemic inflammation ( CSI) can also impair normal immune function, leading to increased susceptibility to infections and tumors and poor response to vaccines. Furthermore, ICS during pregnancy and childhood can have serious developmental consequences, including increased risk of noncommunicable diseases throughout life.

Although the acute inflammatory response shares some common mechanisms with ICS, the two differ.

Most notably, the acute inflammatory response is typically initiated during the infectious process, by the interaction between pattern recognition receptors, expressed in innate immune cells, and evolutionarily conserved structures in pathogens. These patterns are called pathogen-associated molecular patterns (PMAPs).

The acute inflammatory response can also be activated by damage-associated molecular patterns (DAPs), which are released in response to harmful physical, chemical or metabolic stimuli, that is, "sterile" agents during stress or cellular damage. After infection, the production of molecules such as lipoxins, resolvins, maresins and proteins contribute to the resolution of inflammation.

In contrast, in the absence of an acute infectious insult or PMAP activation, ICS is usually caused by PMAD. ICS often increases with age, as indicated by studies showing that older people have higher levels of circulating cytokines, chemokines, and acute phase proteins, as well as greater expression of genes involved in inflammation. On the other hand, over time, low-grade and persistent ICS finally causes collateral damage to tissues and organs, by inducing oxidative stress.

Empirical evidence that inflammation mediates disease onset or progression is strongest for metabolic syndrome, type 2 diabetes, and cardiovascular disease. In fact, a meta-analysis of more than 160,000 people participating in 54 long-term prospective studies showed that circulating CRP levels were associated with a relative increased risk of coronary heart disease and mortality from cardiovascular disease.

The most compelling evidence for an association between ICS and disease risk comes from randomized controlled trials that have tested drugs or biologics targeting specific proinflammatory cytokines, such as IL-1β and tumor necrosis factor (TNF)-α. A recent meta-analysis of 8 randomized controlled trials found that treatment with TNF-α inhibitors significantly reduced insulin resistance in patients with rheumatoid arthritis and improved their insulin sensitivity.

The risk of developing Alzheimer ’s disease was also significantly lower among rheumatoid arthritis patients treated with the TNFα inhibitor etanercept. Furthermore, a recent double-blind randomized controlled study of the IL1β inhibitor canakinumab, which evaluated more than 10,000 adults with a history of myocardial infarction and elevated circulating CRP levels, showed that patients treated with subcutaneous canakinumab every 3 months had lower rates of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular disease compared with those treated with placebo, despite no change in LDL cholesterol, which is a risk factor for the disease cardiovascular.

Another recent English study, with the same characteristics, found a combination of inflammatory markers based on CRP (>10 mg/l), albumin (>35 mg/l) and neutrophil count, predicted overall mortality over 8 years, in addition to mortality from cancer and cardiovascular and cerebrovascular diseases.

Several causes of low-grade chronic systemic inflammation (SCI) and their consequences have been identified. As shown on the left, the most common triggers for SCI (counterclockwise) include chronic infections, physical inactivity, obesity (visceral), gut dysbiosis, diet, social isolation, psychological stress, disturbed sleep and circadian rhythm, and exposure to xenobiotics such as air pollutants, hazardous waste products, industrial chemicals, and tobacco smoking. As shown on the right, the consequences of SCI (clockwise) include metabolic syndrome, type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, cancer, depression, autoimmune diseases, neurodegenerative diseases, sarcopenia, osteoporosis and immunosenescence.

Despite evidence linking ICS to the risk of disease and mortality, there are currently no standard biomarkers that indicate the presence of chronic inflammation, which is detrimental to health. Some studies have shown that canonical biomarkers of acute inflammation predict morbidity and mortality, both in cross-sectional and longitudinal studies, and therefore can be used to index age-related ICS.

This approach has notable limitations, for example, regarding the relationship with monocytes and cytokines, due to its contradictory results. There is evidence that in advanced age it is associated with greater inflammatory activity, but this is not the case with all inflammatory markers, and it is possible that these associations are due, at least in part, to the increase in chronic diseases and frailty that They are often associated with age rather than with the biology of aging itself.

To address the limitations associated with evaluating only a few selected inflammatory biomarkers, some researchers have employed a multidimensional approach that involves analyzing large numbers of inflammatory markers and then combining them into more reliable indices, representative of greater inflammatory activity. In one of these studies, principal component analysis was done to identify pro- and anti-inflammatory markers and the innate immune system response that significantly predicted the risk of various chronic diseases, as well as mortality.

More recently, a multi-omics approach has been applied to examine links between ICS and disease risk. The researchers longitudinally followed 135 adults and established a deep molecular profile of gene expression from the participants’ whole blood, called the transcriptome ; immunological proteins e.g. cytokines and chemokines called immunomes and, frequencies of cell subsets such as CD8+ T cell subsets, monocytes, natural killer cells, B cells and CD4+ T cell subsets.

This allowed us to build a high-dimensional trajectory of immunological aging , which turned out to be better than chronological age at describing how people’s immunity works.

This new metric, in turn, accurately predicted all-cause mortality, which in the future could serve to identify patient risk in clinical settings. These integrative, multilevel approaches aimed at characterizing ICS are very promising, but still, the authors say, we are in a preliminary stage.

In older people, the state of the spinal cord is thought to be due, in part, to a complex process called cellular senescence , characterized by the arrest of cellular proliferation and the development of a multifaceted senescence-associated secretory phenotype.

A prominent feature of this phenotype is the increased secretion of proinflammatory cytokines, chemokines, and other cellular proinflammatory molecules. In turn, senescent cells expressed by this phenotype can promote numerous chronic diseases, including insulin resistance, cardiovascular diseases, pulmonary hypertension, chronic obstructive pulmonary disease, emphysema, Alzheimer’s and Parkinson’s diseases, degeneration macular, osteoarthritis and cancer.

How senescent cells acquire the senescence-associated secretory phenotype is not completely understood, but is believed to be a combination of endogenous and social, environmental, and lifestyle risk factors. Known endogenous causes of this phenotype include: DNA damage, dysfunctional telomeres, epigenomic alteration, mitogenic signals and oxidative stress.

Non-endogenous contributors are thought to include: chronic infections, lifestyle-induced obesity, microbiome dysbiosis, diet, social and cultural changes, and environmental and industrial toxicants. The fact that differences exist in the extent to which older adults have ICS is believed to be indicative of interindividual differences in exposure to these and other related proinflammatory factors, although there are few studies documenting individual associations with these risk factors and ICS.

However, differences in non-communicable diseases associated with ICS are evident between different cultures and countries. It is very notable that rates of ICS-related diseases have increased dramatically in both older and younger people living in industrialized countries and following a Western lifestyle, but are relatively rare in individuals from non-industrial populations. Westernized , those who adhere to diets, lifestyles and ecological niches that most closely resemble those that were present in much of human evolution.

On the other hand, diet and lifestyle, as well as exposure to various pollutants can increase oxidative stress, upregulate mitogenic signaling pathways and cause genomic and epigenomic perturbations that can induce the secretory phenotype associated with senescence.

> Chronic infections

 It is still a matter of controversy whether infections with cytomegalovirus, Epstein-Barr virus, hepatitis C virus and other infectious agents on ICS, throughout life, cause immune dysregulation. From the point of view of aging, chronic cytomegalovirus infection has been associated with the so-called immunological risk phenotype, which in several studies has been predictive of early mortality.

On the other hand, chronic HIV infection causes premature aging of the immune system and is associated with early cardiovascular and skeletal alterations; these effects are largely attributed to the accumulation of senescent CD8+ T cells that elevate proinflammatory mediators.

Although several studies have reported associations between chronic infections and autoimmune diseases, certain cancers, neurodegenerative diseases, and cardiovascular diseases, chronic infections appear to interact synergistically with environmental and genetic factors that influence these health outcomes.

In fact, humans evolved alongside a variety of viruses, bacteria, and other microbes, and while chronic infections appear to contribute to CSI, they are probably not the main drivers.

For example, existing hunter-gatherer populations and other non-industrialized societies, such as the hunter-gatherers of the Ecuadorian Amazon, the Tsimané horticulturist-gatherers of Bolivia, the hunter-gatherers of Tanzania, the rural subsistence farmers of Ghana and traditional gardeners of Kitava (Papua New Guinea)—who are minimally exposed to industrialized environments but highly exposed to varied microbes)—exhibit very low rates of chronic inflammation-related disease and substantial fluctuations in inflammatory markers, which do not increase with age.

> Lifestyle and social and physical environment

Individuals in the aforementioned populations have a relatively short life expectancy on average, meaning that some die before showing signs of advanced aging. However, in these populations, the relative absence of ICS-related health problems has not been attributed to genetics or having a shorter life expectancy but, rather, to lifestyle factors and social and environmental environments. physiques that those people inhabit.

Their lifestyles, for example, are characterized by higher levels of physical activity, diets composed primarily of fresh or minimally processed foods , and lower exposure to environmental pollutants. Furthermore, people living in these environments tend to have circadian rhythms more closely synchronized with diurnal fluctuations in sunlight exposure, and the social stressors they experience are different from those present in industrialized environments.

These social and environmental characteristics are believed to have predominated for most of hominid evolutionary history, until industrialization arrived. This conferred many benefits, including social stability; reducing physical trauma; access to modern medical technology and improved public health measures, such as sanitation, quarantine policies, and vaccination, all of which significantly decrease infant mortality rates and increase average life expectancy.

However, these changes also caused radical changes in diet and lifestyle, with very different results from those that shaped human physiology for most of evolution. This is believed to have created an evolutionary mismatch in humans, characterized by increasing separation from their ecological niche, and this mismatch, in turn, has given rise to the hypothesis that it is an important cause of ICS.

> Physical activity

Industrialization is believed to have caused a significant overall decline in physical activity. One study showed that worldwide, 31% of people are physically inactive, with higher levels of inactivity in high-income countries.

Skeletal muscle is an endocrine organ that produces and releases cytokines and other small proteins (myokines) into the bloodstream. This occurs particularly during muscle contraction and may have the effect of systemically reducing inflammation. Therefore, it has been proven that physical activity is directly related to the increase in anabolic resistance and the levels of CRP and proinflammatory cytokines in healthy individuals, as well as in breast cancer survivors and in patients with type 2 diabetes.

These effects can, in turn, promote several pathophysiological alterations related to inflammation, including insulin resistance, dyslipidemia, endothelial dysfunction, arterial hypertension and loss of muscle mass (sarcopenia), which increase the risk of various cardiovascular diseases, type 2 diabetes, non-alcoholic fatty liver, osteoporosis, various cancers, depression, dementia and Alzheimer’s disease, in chronically inactive people.

Consistent with these effects, there is strong evidence that there is a relationship between physical inactivity and increased risk of age-related diseases and mortality. In a major study, moderate-intensity aerobic activity (50 minutes per week) was associated with a lower risk of mortality from cardiovascular disease and type 2 diabetes.

Finally, physical inactivity can increase the risk of contracting various non-communicable diseases, because it is related to obesity and, in particular, excess visceral adipose tissue (VAT), which is an important trigger of inflammation. The TAV is an active endocrine, immunological and metabolic organ, composed of several cells (e.g., immune, such as resident macrophages) that expands mainly through the hypertrophy of adipocytes, and can generate areas of hypoxia and even cell death. , causing inactivation of inducible factor-1α, hypoxia, increased production of reactive oxygen species, and release of cellular patterns associated with damage (e.g., cell-free DNA).

These events can induce the secretion of numerous proinflammatory molecules : adipokines, cytokines (e.g., IL-1β, IL-6, TNF-α), and chemokines (especially monocyte chemoattractant protein 1) by adipocytes, endothelial, and immune cells. resident adipose tissue (e.g. macrophages). This, in turn, leads to the infiltration of various immune cells into the TAV, including monocytes, neutrophils, dendritic cells, B, T and natural killer cells, lymphocytes and, the reduction of regulatory T cells, thereby increasing the inflammation, which, in some individuals, may eventually become prolonged and systemic.

Furthermore, TNF-α and other molecules can cause insulin resistance of adipocytes, which increases lipolysis, leading to excess lipids in other organs, such as the pancreas and liver, where they can contribute to liver dysfunction. ß cells, hepatic insulin resistance and fatty liver. Therefore, visceral obesity accelerates aging and increases the risk of cardiometabolic, neurodegenerative and autoimmune diseases, as well as several types of cancer.

These dynamics are known to occur in adults and can promote the risk of age-related diseases, but they first emerge during childhood. Therefore, the childhood obesity epidemic could be playing a key role in promoting the risk of inflammation and age-related diseases worldwide.

> Microbiome dysbiosis

Obesity can also lead to ICS through gut mechanisms mediated by microbiomes. In older adults, changes in the gut microbiota appear to influence the outcome of multiple inflammatory pathways. Obesity, which is strongly related to changes in the gut microbiome, has also been associated with increased intestinal paracellular permeability and endotoxemia.

On the other hand, the latter is suspected to be a cause of inflammation, through the activation of the pattern of recognition receptors, such as Toll-like receptors, in immune cells, and of metabolic conditions mediated by inflammation, such as resistance. to insulin. Interestingly, serum concentrations of zonulin , a protein that increases intestinal permeability, appear to be elevated in obese children and adults, and in people with type 2 diabetes, nonalcoholic fatty liver disease, coronary heart disease, polycystic ovary syndrome, autoimmune diseases, and cancer. .

More recently, elevated serum zonulin concentrations have been found to predict inflammation and physical frailty. More generally, it has been hypothesized that there is a complex balance in the intestinal ecosystem that, if disrupted, can compromise its function and integrity and, in turn, cause low-grade ICS.

Therefore, it may be important to identify potential triggers of dysbiosis and intestinal hyperpermeability, which could include overuse of antibiotics, nonsteroidal anti-inflammatory drugs, and proton pump inhibitors; lack of microbial exposure induced by excessive hygiene and reduced contact with animals and natural soils, which is a very recent phenomenon in the history of human evolution and diet.

> Diet

The typical diet that has been widely adopted in many countries over the past 40 years is relatively low in fruits, vegetables and other foods rich in fiber and prebiotics and high in refined grains, alcohol and ultra-processed foods, particularly those containing emulsifiers.

These dietary factors can alter intestinal composition and microbiota function, and are linked to increased intestinal permeability and epigenetic changes in the immune system, ultimately causing low-grade endotoxemia and ICS. However, the influence of diet on inflammation is not limited to these effects.

For example, the end products of lipoxidation and advanced glycation, absorbed orally and formed during food processing, or when foods are cooked at elevated temperatures and low humidity conditions, increase appetite and are related to excess feeding and, therefore, obesity and inflammation.

On the other hand, high-glycemic foods , such as isolated sugars and refined grains, which are common ingredients in most ultra-processed foods, can cause greater oxidative stress, which activates inflammatory genes.

Other dietary components thought to influence inflammation are trans fatty acids and dietary salt. For example, salt has been shown to tilt macrophages toward a pro-inflammatory phenotype characterized by increased differentiation of naïve CD4 + T cells, T helper (TH)-17 cells, which are highly inflammatory and decrease expression and activity. anti-inflammatory regulatory T cells.

On the other hand, high salt intake can cause adverse effects on the composition of the intestinal microbiota, coinciding with the harmful health effects expected from the consumption of foods with a high content of trans fats and salt.

There are other nutritional factors that can also promote inflammation and potentially contribute to the development of ICS. These factors include deficiencies in micronutrients such as zinc and magnesium, which are caused by consuming processed or refined foods, which are low in vitamins and minerals, and have suboptimal levels of omega-3, which affects the resolution phase of the disease. inflammation.

Long-chain omega-3 fatty acids , especially eicosapentaenoic and docosahexaenoic acids, modulate the expression of genes involved in metabolism and inflammation. Even more important is that they are precursors of molecules such as resolvins, maresins and proteins that intervene in the resolution of inflammation. The main contributors to the increasing global incidence of low omega-3 levels are a low intake of fish and a high intake of vegetable oils, which have high amounts of linoleic acid, which displaces omega-3 fatty acids in phospholipids of the cell membrane.

In turn, it has been proven that supplementation with omega-3 fatty acids reduces inflammation and, therefore, can promote health. The evidence linking diet and mortality is solid, demonstrated in different studies. In 2017, a systematic analysis that studied the diet of 195 countries found that the main risk factor for death was dietary deficiency and excessive sodium intake, being responsible for more than half of diet-related deaths.

Finally, when combined with little physical activity, the consumption of hyperpalatable processed foods, high in fat, sugar, salt, and flavoring additives, can cause significant changes in cellular metabolism and lead to increased production (and defective elimination) of dysfunctional organelles, such as mitochondria, and the loss of misfolded and oxidized endogenous molecules.

These altered molecules, which increase with age, can be recognized by innate immune cells as cellular patterns associated with damage.

These cells, in turn, activate the inflammasome machinery , amplify the inflammatory response, and contribute to a biological state that has been termed " inflammmaging ," defined as the long-term result of stimulation. chronic physiological of the innate immune system, which occurs with advanced age.

That is, inflammation involves changes in numerous organ systems, such as the brain, intestine, liver, kidney, adipose tissue and muscle, and is driven by a variety of age-related molecular mechanisms that have been called " the Seven Pillars." of Aging" :

1. adaptation to stress
2. epigenetics
3. inflammation
4. macromolecular damage
5. metabolism
6. proteostasis
7. stem cells and regeneration

> Social and cultural changes

In addition to physical inactivity and diet, the industrial revolution and the modern era have introduced changes in social interactions and sleep quality, which can promote ICS and insulin resistance , which in turn increases the risk of obesity, type 2 diabetes, cardiovascular diseases and global mortality.

On the other hand, psychological stressors that are persistently present in some contemporary work environments can cause physiological changes that disrupt the regulatory capacity of glucocorticoids, with elevation of cortisol, leading to ICS and poor health.

Another feature of modern society that has recently appeared in human evolutionary history is increased exposure to artificial light, especially the blue spectrum, at atypical biological times. This exposure, especially after sunset, increases arousal and alertness at night and therefore causes disruption of the circadian rhythm, which promotes inflammation and is a risk for multiple inflammation-related diseases.

> Environmental and industrial toxins

 The rapid increase in urbanization over the past 200 years has brought with it an unprecedented increase in human exposure to various xenobiotics , including air pollutants, hazardous waste products, and industrial chemicals that promote ICS.

In the US, the Tox21 program has tested more than 9,000 chemicals using more than 1,600 trials and has shown that some of them are related to the alteration of the molecular signaling pathways that underlie inflammation, in exposed people, and with the risks of diseases related to inflammation.

These chemicals are: phthalates, perfluoroalkyl and polyfluoroalkyl, bisphenols, polycyclic aromatic hydrocarbons and flame retardants. These compounds and others promote inflammatory activity through multiple mechanisms, that is, they can be cytotoxic, cause oxidative stress or act as endocrine disruptors, starting in the uterus.

Therefore, these chemicals are suspected to play a causal role in hormone-dependent cancers, metabolic syndrome, type 2 diabetes, hypertension, cardiovascular disease, allergy and asthma, and autoimmune and neurodegenerative diseases.

Smoking is another source of xenobiotics that has been associated with a variety of inflammation-related diseases.

The origin of ICS may also be related to development. It is well established that childhood events significantly impact metabolic and immunological responses in later life, which in turn promote ICS in adulthood. Childhood obesity , for example, is strongly associated with important changes in adipose tissue and metabolic dysfunction causing metabolism-related ICS, or so-called metainflammation.

Because obese children often become obese adolescents and adults, the risk of developing a proinflammatory phenotype also frequently persists in these children into adulthood. Another example of ICS being influenced by early life circumstances is that increased microbial exposure in childhood is associated with a reduced risk of chronic inflammation in adulthood, according to the hygiene , or "old friends" hypotheses ( N . of the T.: vital microbes that have been present in human existence as tolerated latent infections ).

On the other hand, there is evidence that exposure to psychological stress in the first years of life (abuse, neglect, mistreatment, bullying, or living in a low socioeconomic environment) can increase neural responses to threats, potentially upregulating inflammatory activity, alter immunocompetence and cause ICS throughout the life cycle.

There is data showing that even earlier in development, the immune system is programmed during the prenatal stage and can be affected by epigenetic changes induced by maternal environmental exposures (infectious agents, diet, psychological stress and xenobiotics) during intrauterine life, and even before conception, when paternal factors can also have epigenetic effects. Together, these effects create the potential for intergenerational transmission of ICS risk.

In summary , it is believed that maternal inflammation during pregnancy transmits an inflammatory "code" to the offspring through epigenetic modifications, which will lead to a higher risk of ICS in childhood and adulthood and, therefore, the occurrence is more likely. of a wide variety of health problems related to inflammation.

Despite the observation that ICS typically increases with age, most older adults experience downregulation of components of the immune response, leading to increased susceptibility to viral infections and weakened responses to the vaccines. This apparent paradox can be explained by several mechanisms.

Specifically, highly marked ICS can cause low-grade basal constitutive activation of several signaling pathways, such as Janus kinase/signal transducer and activator of transcription (JAK–STAT) in leukocytes, weakening the acute response to multiple stimuli in the immune cells of older adults with chronic inflammation, due to the reduction of the double increase in the phosphorylation levels of these proteins, after cellular stimulation.

Strong ICS has also been shown to predict poor response to hepatitis B vaccine in humans. Additionally, there is evidence that certain inflammatory biomarkers, such as CRP, inversely correlate with older adults’ response to other vaccines, such as the shingles vaccine. Interestingly, the authors say, this also appears to be true for younger individuals.

This research shows that ICS is associated with a higher risk of developing various chronic diseases that dominate morbidity and mortality. Further studies that collect data on multiple factors affecting ICS are required to have a more complete picture of how exposures and experiences identified at different levels of analysis combine to affect ICS and the risk of inflammation-related diseases.

Robust integrative ICS biomarkers , which go beyond the combination of a few canonical biomarkers of inflammation, are urgently needed . Existing biomarkers, which have primarily included CRP, IL-1β, IL-6, and TNF-α, have been useful in demonstrating that inflammatory activity is related to the risk of disease and mortality, but they only provide limited mechanistic information and do not address anti-inflammatory regulatory pathways that may also be important in influencing the risk of inflammation-related diseases.

Therefore, future research should focus on other biomarkers that have substantial variability between individuals, such as CD8+ T cell subsets, monocytes, NK cells, B cells, and CD4+ T cell subsets. Molecular, transcriptional and proteomic markers of ICS are also required.

Biomarkers that integrate information from various data sources and levels of analysis are needed to represent inflammatory activity and immune regulation and deregulation, as is the application of multi-omics approaches, computational modeling and artificial intelligence to study how mechanisms related to ICS both change and predict changes in the clinical status of individuals throughout life.

Given the difficulty associated with experimenting by manipulating factors such as diet, sleep, and stress levels that affect inflammation, most studies conducted so far have collected inflammatory biomarker data under basal conditions that have not challenged the immune system.

Finally, although many of the ICS-promoting factors mentioned here are at least partially modifiable, including physical inactivity, poor diet, nocturnal exposure to blue light, smoking, environmental and exposure to industrial toxicants, and stress Psychologically, the number of studies that have successfully focused on these risk factors and corresponding reductions in ICS levels are limited.

This has occurred despite the fact that the association between inflammation and chronic diseases is now recognized and health systems are in serious trouble due to the enormous cost of treating a global population that suffers a heavy burden of chronic diseases related to chronic inflammation. systemic. Therefore, it is time to start seriously studying how to prevent and treat the risk of diseases related to chronic systemic inflammation in children and adults.