Indeed, chronic inflammatory diseases have been recognized as the most significant cause of death in the world today, with more than 50% of all deaths being attributable to inflammation-related diseases such as ischemic heart disease, stroke, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease (NAFLD) and autoimmune and neurodegenerative conditions5.
Evidence is emerging that the risk of developing chronic inflammation can be traced back to early development, and its effects are now known to persist throughout the life span to affect adulthood health and risk of mortality6–8.
Inflammation
Inflammation is an evolutionarily conserved process characterized by the activation of immune and non-immune cells that protect the host from bacteria, viruses, toxins and infections by eliminating pathogens and promoting tissue repair and recovery2,9.
Specific biobehavioral effects of inflammation thus include a constellation of energysaving behaviors commonly known as “sickness behaviors,” such as sadness, anhedonia, fatigue, reduced libido and food intake, altered sleep and social-behavioral withdrawal, as well as increased blood pressure, insulin resistance and dyslipidemia10,13.These behavioral changes can be critical for survival during times of physical injury and microbial threat14.
A normal inflammatory response is characterized by the temporally restricted upregulation of inflammatory activity that occurs when a threat is present and that resolves once the threat has passed9,13,15. However, the presence of certain social, psychological, environmental and biological factors has been linked to the prevention of resolution of acute inflammation and, in turn, the promotion of a state of low-grade, non-infective (that is, ‘sterile’) systemic chronic inflammation (SCI) that is characterized by the activation of immune components that are often distinct from those engaged during an acute immune response13,16.
Shifts in the inflammatory response from short- to long-lived can cause a breakdown of immune tolerance9,15 and lead to major alterations in all tissues and organs, as well as normal cellular physiology, which can increase the risk for various non-communicable diseases in both young and older individuals1,9–11,15,17–21. SCI can also impair normal immune function, leading to increased susceptibility to infections and tumors and a poor response to vaccines22–25. Furthermore, SCI during pregnancy and childhood can have serious developmental consequences that include elevating the risk of non-communicable diseases over the life span7,8,26,27.
Systemic chronic inflammation and non-communicable disease risk
Although they share some common mechanisms, the acute inflammatory response differs from SCI (Table 1).
In contrast, SCI is typically triggered by DAMPs in the absence of an acute infectious insult or activation of PAMPs30–32. SCI often increases with age30, as indicated by studies showing that older individuals have higher circulating levels of cytokines, chemokines and acute phase proteins, as well as greater expression of genes involved in inflammation1,19,30.
The clinical consequences of SCI-driven damage can be severe and include increased risk of the metabolic syndrome, which includes the triad of hypertension, hyperglycemia and dyslipidemia33,34; type 2 diabetes33; NAFLD33,35; hypertension1; cardiovascular disease (CVD)18,19; chronic kidney disease19; various types of cancer17; depression21; neurodegenerative and autoimmune diseases4,12,20; osteoporosis11,36 and sarcopenia19 (Fig. 1).
In a recent meta-analysis of eight RCTs that included a total of 260 participants, anti-TNF-α inhibitor therapy was found to significantly reduce insulin resistance in patients with rheumatoid arthritis and to improve their insulin sensitivity42. The risk for developing Alzheimer’s disease was also significantly lower among patients with rheumatoid arthritis treated with the TNF-α inhibitor etanercept43. In addition, a recent double-blind RCT of the IL-1β inhibitor canakinumab that assessed more than 10,000 adults with a history of myocardial infarction and elevated circulating CRP levels showed that patients treated with canakinumab subcutaneously every 3 months had lower rates of nonfatal myocardial infarction, nonfatal stroke and CVD death compared with those treated with a placebo, despite having no change in LDL cholesterol, which is a risk factor for CVD.
Biomarkers for systemic chronic inflammation
Despite evidence linking SCI with disease risk and mortality45, there are presently no standard biomarkers for indicating the presence of health-damaging chronic inflammation. Studies have shown that canonical biomarkers of acute inflammation predict morbidity and mortality in both cross-sectional and longitudinal studies and may thus be used to index age-related SCI46. This approach has notable limitations, though. For example, early work by Roubenoff and colleagues showed that in monocytes from ambulatory individuals, levels of IL-6 and IL-1Ra (but not IL-1β or TNF-α) increased with age47. However, no difference in IL-1 and IL-6 expression has been found between young and older individuals when the health status of older individuals is strictly controlled48,49.
Therefore, evidence exists that greater inflammatory activity is associated with older age, but this is not true of all inflammatory markers, and it is possible that these associations are due at least in part to increases in chronic ailments and frailty that are frequently associated with age rather than to biological aging itself.
To address limitations associated with assessing only a few select inflammatory biomarkers, some researchers have employed a multi-dimensional approach that involves assaying large numbers of inflammatory markers and then combining these markers into more robust indices representing heightened inflammatory activity. In one such study, researchers used principal component analysis to identify pro- and anti-inflammatory markers and an innate immune response that significantly predicted risk for multiple chronic diseases (CVD, kidney disease and diabetes), in addition to mortality51.
More recently, a multi-omics approach has been applied to examine links between SCI and disease risk. The researchers followed 135 adults longitudinally and conducted deep molecular profiling of participants’ whole-blood gene expression, termed the transcriptome; immune proteins—for example, cytokines and chemokines— termed the immunome; and cell subset frequencies, such as CD8+ T cell subsets, monocytes, natural killer (NK) cells, B cells and CD4+ T cell subsets. This enabled the researchers to construct a high-dimensional trajectory of immune aging (IMM-AGE) that described individuals’ immune functioning better than their chronological age. This new metric in turn accurately predicted all-cause mortality, establishing its potential future use for identifying at-risk patients in clinical settings52.
Sources of systemic chronic inflammation
The SCI state in older individuals is thought to be caused in part by a complex process called cellular senescence, which is characterized by an arrest of cell proliferation and the development of a multifaceted senescence-associated secretory phenotype (SASP)53. A prominent feature of this phenotype is increased secretion of proinflammatory
How senescent cells acquire the SASP is not fully understood, but existing research points to a combination of both endogenous and non-endogenous social, environmental and lifestyle risk factors. Among the known endogenous causes of this phenotype are DNA damage, dysfunctional telomeres, epigenomic disruption, mitogenic signals and oxidative stress56. The non-endogenous contributors are thought to include chronic infections57, lifestyle-induced obesity58, microbiome dysbiosis59, diet60, social and cultural changes61,62 and environmental and industrial toxicants63.
Further evidence for a role of lifestyle in the development of chronic inflammation comes from a study of 210 healthy twins between 8 and 82 years old, which found that non-heritable factors are the strongest contributors to differences in chronic inflammation across individuals72 and that exposure to environmental factors, which have been collectively called the exposome, are the main drivers of SCI.
Chronic infections
Although several studies have reported associations between chronic infections and autoimmune diseases, certain cancers, neurodegenerative diseases and CVD, chronic infections appear to interact synergistically with environmental and genetic factors to influence these health outcomes76,77,81.
Lifestyle, social and physical environment
Individuals in the populations mentioned above have relatively short life expectancies on average, which means that some die before showing signs of advanced aging. However, the relative absence of SCI-related health problems in these populations has not been attributed to genetics or to having a shorter life expectancy, but rather to lifestyle factors and the social and physical environments the people inhabit66.
Physical activity
Skeletal muscle is an endocrine organ that produces and releases cytokines and other small proteins, called myokines, into the bloodstream. This occurs particularly during muscle contraction and can have the effect of systemically reducing inflammation95. Low physical activity, therefore, has been found to be directly related to increased anabolic resistance96 and levels of CRP and pro-inflammatory cytokine levels in healthy individuals97, as well as in breast cancer survivors98 and patients with type 2 diabetes99.
Microbiome dysbiosis
Obesity may also lead to SCI through gut microbiome-mediated mechanisms114.
Diet
The typical diet that has become widely adopted in many countries over the past 40 years is relatively low in fruits, vegetables and other fiber- and prebiotic-rich foods66,123–125 and high in refined grains124, alcohol126 and ultra-processed foods125, particularly those containing emulsifiers127. These dietary factors can alter the gut microbiota composition and function123,127–130 and are linked to increased intestinal permeability129–131 and epigenetic changes in the immune system129 that ultimately cause low-grade endotoxemia and SCI129–131.
Other dietary components that are thought to influence inflammation include trans fatty acids134 and dietary salt. For example, salt has been shown to skew macrophages toward a pro-inflammatory phenotype characterized by the increased differentiation of naïve CD4+ T cells into T helper (TH)-17 cells, which are highly inflammatory, and decreased expression and anti-inflammatory activity of T regulatory cells135.
Finally, when combined with low physical activity, consuming hyperpalatable processed foods that are high in fat, sugar, salt and flavor additives147 can cause major changes in cell metabolism and lead to the increased production (and defective disposal) of dysfunctional organelles such as mitochondria, as well as to misplaced, misfolded and oxidized endogenous molecules30,60,148.
Social and cultural changes
In addition to physical inactivity and diet, the industrial revolution and modern era have ushered in changes in social interactions and sleep quality59,91 that can promote SCI149,150 and insulin resistance151, in turn increasing risk for obesity, type 2 diabetes, CVD and all-cause mortality150–154.
As proposed, inflammaging involves changes in numerous organ systems, such as the brain, gut, liver, kidney, adipose tissue and muscle19, and it is driven by a variety of molecular-age-related mechanisms that have been called the “Seven Pillars of Aging”55—namely, adaptation to stress, epigenetics, inflammation, macromolecular damage, metabolism, proteostasis and stem cells and regeneration.
Environmental and industrial toxicants
The rapid rise in urbanization over the past 200 years8 brought with it an unprecedented increase in humans’ exposure to various xenobiotics, including air pollutants, hazardous waste products and industrial chemicals that promote SCI8,161. Each year, an estimated 2,000 new chemicals are introduced into items that individuals use or ingest daily, including foods, personal care products, prescription drugs, household cleaners and lawn care products (see https://ntp.niehs.nih.gov).
The Tox21 Program has tested more than 9,000 chemicals using more than 1,600 assays and has demonstrated that numerous chemicals to which people are commonly exposed greatly alter molecular signaling pathways that underlie inflammation and inflammation-related disease risk164. These chemicals include phthalates, per- and polyfluoroalkyl substances, bisphenols, polycyclic aromatic hydrocarbons and flame retardants165.
These compounds and others promote inflammatory activity via multiple mechanisms. For example, they can be cytotoxic8,162, cause oxidative stress or act as endocrine disruptors, starting in utero8.
Chronic inflammation and the immune response to acute challenges
Despite the observation that SCI generally increases with age, a majority of older adults experience a down-regulation of components of the immune response that leads to an increased susceptibility to viral infections and weakened responses to vaccines. This apparent paradox (Fig. 3) can be explained by several mechanisms. Specifically, elevated SCI can lead to a basal low-grade constitutive activation of various signaling pathways, such as the Janus kinase/signal transducers and activators of transcription (JAK– STAT) system in leukocytes, which results in a weakened acute response to multiple stimuli in immune cells from older adults with chronic inflammation due to reduced fold-increase in the levels of phosphorylation of these proteins after cell stimulation22.
Future directions
Considered together, this body of research provides converging evidence that SCI is associated with increased risk for developing a variety of chronic diseases that dominate present-day morbidity and mortality worldwide and that cause enormous amounts of human suffering.
First, there is a clear need for additional studies that collect data on multiple factors affecting SCI to form a more comprehensive picture of how exposures and experiences identified at different levels of analysis combine to affect SCI and inflammation-related disease risk. Second, the field sorely needs robust integrative biomarkers of SCI that go beyond combining a few canonical biomarkers of acute inflammation. Existing biomarkers, which have primarily included CRP, IL-1β, IL-6 and TNF-α, have been useful for demonstrating that inflammatory activity is related to disease and mortality risk, but these markers provide only limited mechanistic information (given the enormous complexity of the inflammatory response) and they do not address anti-inflammatory regulatory pathways that may also be relevant for influencing inflammation-related disease risk.
Third, given the difficulty associated with experimentally manipulating factors such as diet, sleep and stress levels that affect inflammation, a majority of studies conducted thus far have collected inflammatory biomarker data under basal conditions in which the immune system is not challenged.
Finally, although many of the SCI-promoting factors that we have described herein are at least partly modifiable—including physical inactivity, poor diet, nighttime blue light exposure, tobacco smoking, environmental and industrial toxicants exposure and psychological stress—the number of studies that have successfully targeted these risk factors and shown corresponding reductions in SCI levels is limited.
Nat Med. 2019 Dec;25(12):1822-1832