Chronic inflammation in the etiology of disease across the life span

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 recovery^2,9. Depending on the degree and extent of the inflammatory response, including whether it is systemic or local, metabolic and neuroendocrine changes can occur to conserve metabolic energy and allocate more nutrients to the activated immune system^9–12. Specific biobehavioral effects of inflammation thus include a constellation of energy-saving 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 dyslipidemia^10,13.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 passed^9,13,15. 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 response^13,16.

Shifts in the inflammatory response from short- to long-lived can cause a breakdown of immune tolerance^9,15 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 individuals^{1,9–11,15,17–21}. SCI can also impair normal immune function, leading to increased susceptibility to infections and tumors and a poor response to vaccines^22–25. Furthermore, SCI during pregnancy and childhood can have serious developmental consequences that include elevating the risk of non-communicable diseases over the life span^7,8,26,27.

Systemic chronic inflammation and non-communicable disease risk

Although they share some common mechanisms, the acute inflammatory response differs from SCI (Table 1). Most notably, the acute inflammatory response is typically initiated during times of infection via an interaction between pattern recognition receptors expressed on innate immune cells and evolutionarily conserved structures on pathogens, called pathogen-associated molecular patterns (PAMPs). The acute inflammatory response can also be activated by damage-associated molecular patterns (DAMPs) that are released in response to physical, chemical or metabolic noxious stimuli—that is, ‘sterile’ agents—during cellular stress or damage². Following infection, production of molecules such as lipoxins, resolvins, maresins and protectins then contribute to the resolution of inflammation^28,29.

In contrast, SCI is typically triggered by DAMPs in the absence of an acute infectious insult or activation of PAMPs^30–32. 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 inflammation^1,19,30. Moreover, SCI is low-grade and persistent (as the name suggests) and ultimately causes collateral damage to tissues and organs over time, such as by inducing oxidative stress^1,4,9,19.

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 dyslipidemia^33,34; type 2 diabetes³³; NAFLD^33,35; hypertension¹; cardiovascular disease (CVD)^18,19; chronic kidney disease¹⁹; various types of cancer¹⁷; depression²¹; neurodegenerative and autoimmune diseases^4,12,20; osteoporosis^11,36 and sarcopenia¹⁹ (Fig. 1). Empirical evidence that inflammation plays a role in disease onset or progression is strongest for metabolic syndrome, type 2 diabetes and CVD. Indeed, it has long been known that patients with autoimmune diseases such as rheumatoid arthritis that are characterized by systemic inflammation have insulin resistance, dyslipidemia and hypertension, and that they have higher rates of metabolic syndrome, type 2 diabetes and CVD (particularly ischemic heart disease and str oke)^{10,12,37–39}. Moreover, the inflammatory biomarker high-sensitivity C-reactive protein (CRP) is a predictor of cardiovascular events in men and women⁴⁰. In a recent meta-analysis of data from more than 160,000 people across 54 long-term prospective studies, higher levels of circulating CRP were associated with a relative increase in risk for both coronary heart disease and CVD mortality⁴¹.

The most compelling evidence for an association between SCI and disease risk comes from randomized controlled trials (RCTs) that have tested drugs or biologics that target specific pro-inflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α. 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. In this trial, canakinumab-treated patients also exhibited a lower likelihood of unstable angina leading to urgent revascularization⁴⁴.

Along similar lines, a recent study of more than 160,000 people from North Glasgow found that a combination of the inflammatory markers CRP (>10 mg/L; HR 2.71, P < 0.001), albumin (>35 mg/L; HR 3.68, P < 0.001) and neutrophil count (HR 2.18, P < 0.001) predicted all-cause mortality over 8 years, in addition to mortality due to cancer, cardiovascular and cerebrovascular disease⁴⁵.

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 controlled^48,49.

Additionally, a recent study examined levels of 18 endogenous and ex vivo-stimulated inflammatory markers in 41 healthy volunteers of different ages across the life span. Results revealed that unstimulated levels of IL-12p70 in women and CRP in men were associated with older age, whereas no effects were found for IL-1β, IFN-α or TNF-α⁵⁰. 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. These types of integrative, multi-level approaches to characterizing SCI are promising, but this work is still in its infancy and much more research is needed to identify best practices for selecting and analyzing SCI-related biomarkers in order to yield the most useful and predictive information for quantifying age-related disease risk.

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 pro-inflammatory cytokines, chemokines and other pro-inflammatory molecules from cells⁵³. Senescent cells expressing this phenotype can in turn promote a multitude of chronic health conditions and diseases, including insulin resistance, CVD, pulmonary arterial hypertension, chronic obstructive pulmonary disorder, emphysema, Alzheimer’s and Parkinson’s diseases, macular degeneration, osteoarthritis and cancer^54,55.

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 changes^61,62 and environmental and industrial toxicants⁶³. The fact that differences exist in the extent to which older adults exhibit SCI^52,64 is thought to be indicative of inter-individual differences in exposure to these and other related pro-inflammatory factors, although studies documenting within-person associations between these risk factors and SCI are limited.

Nevertheless, differences in non-communicable diseases associated with SCI are evident across cultures and countries. Most prominently, SCI-related disease rates have increased dramatically for both older and younger individuals living in industrialized countries who follow a Western lifestyle but are relatively rare among individuals in non-Westernized populations who adhere to diets, lifestyles and ecological niches that more closely resemble those present during most of human evolution^65–71. Furthermore, dietary and lifestyle habits, as well as exposure to a variety of different pollutants, can increase oxidative stress, upregulate mitogenic signaling pathways and cause genomic and epigenomic perturbations^8,60,62,63 that can induce the SASP. 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. Simply put, the exposome refers to a person’s lifelong exposure to physical, chemical and biological elements, starting from the prenatal period onward⁷³.

Developmental origins of systemic chronic inflammation

The origins of SCI can also be viewed from a developmental perspective. For example, it is well established that childhood circumstances significantly impact metabolic and immune responses later in life, which in turn promote SCI in adulthood^{8,26,27,168,169}. Childhood obesity, for instance, is strongly associated with major changes in adipose tissue and metabolic dysfunction that cause metabolism-related-SCI, or so-called metainflammation²⁶. Because obese children often become obese adolescents and adults²⁶, the risk of developing a pro-inflammatory phenotype also frequently persists into adulthood among individuals who were obese as children.

Another example of SCI being influenced by early life circumstances comes from epidemiologic studies showing that greater microbial exposure in infancy is associated with reduced risk of chronic inflammation in adulthood^8,168, as predicted by the hygiene, or ‘old friends’, hypothesis⁸². Additionally, there is evidence that exposure to psychological stress early in life—for example, in the form of abuse, neglect, maltreatment, bullying or living in a low socioeconomic environment—can heighten neural responses to threat that can upregulate inflammatory activity¹⁷⁰, alter immuno-competence and lead to SCI throughout the lifecycle^27,169.

Further back in the developmental trajectory are data showing that the immune system is programmed during the prenatal period¹⁷¹ and is affected by epigenetic changes induced by maternal environmental exposures (for example, infectious agents, diet, psychological stress and xenobiotics) during intrauterine life and even before conception, when paternal factors may also have an epigenetic effect^26,128,171. Together, these effects create the potential for the intergenerational transmission of risk for SCI. In this model (Fig. 2), SCI and disease risk are hypothesized to be perpetuated transgenerationally. In short, maternal inflammation during pregnancy^172,173 is believed to pass an inflammatory ‘code’ through epigenetic modifications to the offspring, who will exhibit elevated risk for SCI in childhood and adulthood and therefore be more likely to suffer from a wide variety of inflammation-related health problems, including obesity⁷, CVD⁷, cancer¹⁷⁴ and neurological illness¹⁷⁵, among others, only to again pass this risk on to their own offspring.

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. Elevated SCI has also been shown to predict hyporesponsiveness to the hepatitis B vaccine in humans²⁴. Additionally, there is evidence that certain inflammatory biomarkers, such as CRP, are inversely correlated with older adults’ response to other vaccines, such as the herpes zoster vaccine²³. Interestingly, this also seems to be true for younger individuals. Among adolescents, for example, those who respond well to typhoid vaccination have been found to exhibit lower concentrations of CRP than non-responders in adulthood²⁵. In sum, this research helps to explain the pro-inflammatory/antiviral skewing that occurs as individuals age. This work also suggests that exposure to an inflammatory environment early in life is an important determinant of multiple aspects of an individual’s immuno-phenotype in adulthood.

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. At the same time, there are several key avenues that could be pursued to help strengthen this work and translate this research into effective strategies for improving human health.

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. Future research should thus focus on additional biomarkers that have been found to have substantial variability across individuals, such as CD8⁺ T cell subsets, monocytes, NK cells, B cells and CD4⁺ T cell subsets¹⁷⁶. This work should also include molecular, transcriptional and proteomic markers of SCI, which have only been examined in limited ways to date¹⁷⁷. Constructing biomarkers that integrate information from a variety of different data sources and levels of analysis to represent inflammatory activity and immune regulation and dysregulation would be particularly useful, as would applying multi-omics approaches, computational modeling and artificial intelligence to study how SCI-related mechanisms both change and predict changes in clinical status within individuals over the life span¹⁷⁸.

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. This is a sensible starting place, but such research does not provide any information regarding biological reactivity or recovery (for example, from infection or psychological or physiological stress), which may ultimately be most useful for understanding individual differences in inflammation-related disease risk^3,179. Finally, although many of the SCI-promoting factors that we have described herein are at least partly modifiable—including physical inactivity, poor diet, night-time 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. This has occurred despite the fact that the association between inflammation and chronic disease is now widely recognized and that healthcare systems are buckling due to the enormous cost of treating a worldwide population that is heavily burdened by SCI-related chronic health problems. Therefore, the time to start seriously studying how to prevent and treat SCI-related disease risk in both children and adults is now.

In conclusion, we have a long way to go before we fully understand the role that SCI plays in disease risk, biological aging and mortality. For example, no study to date has assessed the entire human exposome over the entire developmental trajectory, starting in utero (for example, by measuring maternal exposures, type of delivery and early-life nutrition) and continuing into adulthood (for example, by assessing social and cultural processes, xenobiotic exposures, individual lifestyle habits, lifelong antibiotic use, vaccinations, infectious diseases and social-psychological stressors). Moreover, only a few studies have investigated how modifying SCI-related processes may benefit human health or longevity. As a result, although SCI is a highly modifiable process in principle, additional research, initiative and investment are needed before we fully realize the potential benefits associated with targeting inflammation to improve human health.