Chronic Inflammation in The Etiology of Disease

Perspective
https://doi.org/10.1038/s41591-019-0675-0
Chronic inflammation in the etiology of disease

across the life span
David Furman 1,2,3,4*, Judith Campisi1,5, Eric Verdin 1, Pedro Carrera-Bastos6, Sasha Targ4,7,
Claudio Franceschi8,9, Luigi Ferrucci10, Derek W. Gilroy11, Alessio Fasano 12, Gary W. Miller13,
Andrew H. Miller14, Alberto Mantovani 15,16,17, Cornelia M. Weyand 18, Nir Barzilai19,
Jorg J. Goronzy 20, Thomas A. Rando20,21,22, Rita B. Effros23, Alejandro Lucia24,25,
Nicole Kleinstreuer 26,27 and George M. Slavich 28
Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research
has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can,
in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as
cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and
neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several
risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental
and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagno-
sis, prevention and treatment of SCI.
O
ne of the most important medical discoveries of the past two mortality6–8. In this Perspective, we describe these effects and out-
decades has been that the immune system and inflamma- line some promising avenues for future research and intervention.
tory processes are involved in not just a few select disorders,
but a wide variety of mental and physical health problems that dom- Inflammation
inate present-day morbidity and mortality worldwide1–4. Indeed, Inflammation is an evolutionarily conserved process characterized
chronic inflammatory diseases have been recognized as the most by the activation of immune and non-immune cells that protect the
significant cause of death in the world today, with more than 50% of host from bacteria, viruses, toxins and infections by eliminating
all deaths being attributable to inflammation-related diseases such pathogens and promoting tissue repair and recovery2,9. Depending
as ischemic heart disease, stroke, cancer, diabetes mellitus, chronic on the degree and extent of the inflammatory response, includ-
kidney disease, non-alcoholic fatty liver disease (NAFLD) and auto- ing whether it is systemic or local, metabolic and neuroendocrine
immune and neurodegenerative conditions5. Evidence is emerg- changes can occur to conserve metabolic energy and allocate more
ing that the risk of developing chronic inflammation can be traced nutrients to the activated immune system9–12. Specific biobehav-
back to early development, and its effects are now known to per- ioral effects of inflammation thus include a constellation of energy-
sist throughout the life span to affect adulthood health and risk of saving behaviors commonly known as “sickness behaviors,” such as
1
Buck Institute for Research on Aging, Novato, CA, USA. 2Stanford 1000 Immunomes Project, Institute for Immunity, Transplantation and Infection,
Stanford University School of Medicine, Stanford, CA, USA. 3Institute for Research in Translational Medicine, Universidad Austral, CONICET, Pilar, Buenos
Aires, Argentina. 4Iuve Inc., San Mateo, CA, USA. 5Lawrence Berkeley National Laboratory, Berkeley, CA, USA. 6Center for Primary Health Care Research,
Lund University/Region Skåne, Skåne University Hospital, Malmö, Sweden. 7Medical Scientist Training Program, University of California, San Francisco,
San Francisco, CA, USA. 8IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy. 9Department of Applied Mathematics and Laboratory of
Systems Biology of Aging, Lobachevsky University, Nizhny Novgorod, Russia. 10Translational Gerontology Branch, National Institute on Aging, National
Institutes of Health, Baltimore, MD, USA. 11Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London,
UK. 12MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, USA. 13Department of Environmental Health Sciences, School of Public
Health, Columbia University Medical Center, New York, NY, USA. 14Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, GA, USA. 15Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 16Department of Biomedical Sciences, Humanitas University,
Pieve Emanuele, Milan, Italy. 17William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University, London, UK. 18Division
of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA. 19Departments of Medicine and Genetics, Albert
Einstein College of Medicine, New York, NY, USA. 20Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA,
USA. 21Center for Tissue Regeneration, Repair and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA. 22Department of
Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. 23Department of Pathology, University of California,
Los Angeles, Los Angeles, CA, USA. 24Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, Spain. 25Research Institute of the Hospital 12
de Octubre (i+12), Madrid, Spain. 26Biostatistics and Computational Biology Branch, Division of Intramural Research, National Institute of Environmental
Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA. 27NTP Interagency Center
for the Evaluation of Alternative Toxicological Methods, National Institute of Environmental Health Sciences, National Institutes of Health, Department
of Health and Human Services, Research Triangle Park, NC, USA. 28Cousins Center for Psychoneuroimmunology and Department of Psychiatry and
Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA. *e-mail: furmand@stanford.edu
1822 Nature Medicine | VOL 25 | December 2019 | 1822–1832 | www.nature.com/naturemedicine

NATure MedICIne Perspective
sadness, anhedonia, fatigue, reduced libido and food intake, altered
Table 1 | Acute inflammation versus systemic chronic
sleep and social-behavioral withdrawal, as well as increased blood
inflammation
pressure, insulin resistance and dyslipidemia10,13.These behavioral
changes can be critical for survival during times of physical injury Acute inflammation Systemic chronic inflammation
and microbial threat14. Trigger PAMPs (infection), DAMPs (‘exposome’, metabolic
A normal inflammatory response is characterized by the tem- DAMPs (cellular dysfunction, tissue damage)
porally restricted upregulation of inflammatory activity that occurs stress, trauma)
when a threat is present and that resolves once the threat has
Duration Short-term Persistent, non-resolving
passed9,13,15. However, the presence of certain social, psychological,
environmental and biological factors has been linked to the preven- Magnitude High-grade Low-grade
tion of resolution of acute inflammation and, in turn, the promo- Outcome(s) Healing, trigger Collateral damage
tion of a state of low-grade, non-infective (that is, ‘sterile’) systemic removal, tissue repair
chronic inflammation (SCI) that is characterized by the activation Age-related No Yes
of immune components that are often distinct from those engaged
during an acute immune response13,16. Biomarkers IL-6, TNF-α, IL-1β, CRP Silent—no canonical standard
biomarkers
Shifts in the inflammatory response from short- to long-lived
can cause a breakdown of immune tolerance9,15 and lead to major DAMP, damage-associated molecular pattern; PAMP, pathogen-associated molecular pattern.
alterations in all tissues and organs, as well as normal cellular physi-
ology, which can increase the risk for various non-communicable
diseases in both young and older individuals1,9–11,15,17–21. SCI can also than 160,000 people across 54 long-term prospective studies, higher
impair normal immune function, leading to increased susceptibil- levels of circulating CRP were associated with a relative increase in
ity to infections and tumors and a poor response to vaccines22–25. risk for both coronary heart disease and CVD mortality41.
Furthermore, SCI during pregnancy and childhood can have seri- The most compelling evidence for an association between SCI
ous developmental consequences that include elevating the risk of and disease risk comes from randomized controlled trials (RCTs)
non-communicable diseases over the life span7,8,26,27. that have tested drugs or biologics that target specific pro-inflamma-
tory cytokines, such as interleukin (IL)-1β and tumor necrosis fac-
Systemic chronic inflammation and non-communicable tor (TNF)-α. In a recent meta-analysis of eight RCTs that included
disease risk a total of 260 participants, anti-TNF-α inhibitor therapy was found
Although they share some common mechanisms, the acute inflam- to significantly reduce insulin resistance in patients with rheuma-
matory response differs from SCI (Table 1). Most notably, the toid arthritis and to improve their insulin sensitivity42. The risk for
acute inflammatory response is typically initiated during times of developing Alzheimer’s disease was also significantly lower among
infection via an interaction between pattern recognition receptors patients with rheumatoid arthritis treated with the TNF-α inhibitor
expressed on innate immune cells and evolutionarily conserved etanercept43. In addition, a recent double-blind RCT of the IL-1β
structures on pathogens, called pathogen-associated molecular inhibitor canakinumab that assessed more than 10,000 adults with
patterns (PAMPs). The acute inflammatory response can also be a history of myocardial infarction and elevated circulating CRP lev-
activated by damage-associated molecular patterns (DAMPs) that els showed that patients treated with canakinumab subcutaneously
are released in response to physical, chemical or metabolic noxious every 3 months had lower rates of nonfatal myocardial infarction,
stimuli—that is, ‘sterile’ agents—during cellular stress or damage2. nonfatal stroke and CVD death compared with those treated with
Following infection, production of molecules such as lipoxins, a placebo, despite having no change in LDL cholesterol, which is a
resolvins, maresins and protectins then contribute to the resolution risk factor for CVD. In this trial, canakinumab-treated patients also
of inflammation28,29. exhibited a lower likelihood of unstable angina leading to urgent
In contrast, SCI is typically triggered by DAMPs in the absence revascularization44.
of an acute infectious insult or activation of PAMPs30–32. SCI often Along similar lines, a recent study of more than 160,000 people
increases with age30, as indicated by studies showing that older indi- from North Glasgow found that a combination of the inflammatory
viduals have higher circulating levels of cytokines, chemokines and markers CRP (>10 mg/L; HR 2.71, P < 0.001), albumin (>35 mg/L;
acute phase proteins, as well as greater expression of genes involved HR 3.68, P < 0.001) and neutrophil count (HR 2.18, P < 0.001) pre-
in inflammation1,19,30. Moreover, SCI is low-grade and persistent (as dicted all-cause mortality over 8 years, in addition to mortality due
the name suggests) and ultimately causes collateral damage to tis- to cancer, cardiovascular and cerebrovascular disease45.
sues and organs over time, such as by inducing oxidative stress1,4,9,19.
The clinical consequences of SCI-driven damage can be severe Biomarkers for systemic chronic inflammation
and include increased risk of the metabolic syndrome, which Despite evidence linking SCI with disease risk and mortality45, there
includes the triad of hypertension, hyperglycemia and dyslipid- are presently no standard biomarkers for indicating the presence of
emia33,34; type 2 diabetes33; NAFLD33,35; hypertension1; cardiovas- health-damaging chronic inflammation. Studies have shown that
cular disease (CVD)18,19; chronic kidney disease19; various types canonical biomarkers of acute inflammation predict morbidity and
of cancer17; depression21; neurodegenerative and autoimmune mortality in both cross-sectional and longitudinal studies and may
diseases4,12,20; osteoporosis11,36 and sarcopenia19 (Fig. 1). Empirical thus be used to index age-related SCI46. This approach has notable
evidence that inflammation plays a role in disease onset or progres- limitations, though. For example, early work by Roubenoff and col-
sion is strongest for metabolic syndrome, type 2 diabetes and CVD. leagues showed that in monocytes from ambulatory individuals,
Indeed, it has long been known that patients with autoimmune dis- levels of IL-6 and IL-1Ra (but not IL-1β or TNF-α) increased with
eases such as rheumatoid arthritis that are characterized by systemic age47. However, no difference in IL-1 and IL-6 expression has been
inflammation have insulin resistance, dyslipidemia and hyperten- found between young and older individuals when the health status
sion, and that they have higher rates of metabolic syndrome, type of older individuals is strictly controlled48,49.
2 diabetes and CVD (particularly ischemic heart disease and str Additionally, a recent study examined levels of 18 endogenous
oke)10,12,37–39. Moreover, the inflammatory biomarker high-sensitiv- and ex vivo-stimulated inflammatory markers in 41 healthy vol-
ity C-reactive protein (CRP) is a predictor of cardiovascular events unteers of different ages across the life span. Results revealed that
in men and women40. In a recent meta-analysis of data from more unstimulated levels of IL-12p70 in women and CRP in men were
Nature Medicine | VOL 25 | December 2019 | 1822–1832 | www.nature.com/naturemedicine 1823

Perspective NATure MedICIne
Cardiovascular Cancer
Chronic disease
Physical infections
inactivity
Metabolic syndrome, Depression
type 2 diabetes
and NAFLD
Obesity
Auto-
immune
diseases
SCI
Dysbiosis
Neurodegenerative
diseases
Diet
Sarcopenia
Immunosenescence and osteoporosis
Xenobiotics
Disturbed
Isolation and sleep
chronic stress
Fig. 1 | Causes and consequences of low-grade systemic chronic inflammation. Several causes of low-grade systemic chronic inflammation (SCI)
and their consequences have been identified. As shown on the left, the most common triggers of SCI (in counter-clockwise direction) include chronic
infections, physical inactivity, (visceral) obesity, intestinal dysbiosis, diet, social isolation, psychological stress, disturbed sleep and disrupted 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 (in clockwise direction) include metabolic syndrome, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), cardiovascular
disease, cancer, depression, autoimmune diseases, neurodegenerative diseases, sarcopenia, osteoporosis and immunosenescence.
associated with older age, whereas no effects were found for IL-1β, order to yield the most useful and predictive information for quan-
IFN-α or TNF-α50. Therefore, evidence exists that greater inflam- tifying age-related disease risk.
matory activity is associated with older age, but this is not true of
all inflammatory markers, and it is possible that these associations Sources of systemic chronic inflammation
are due at least in part to increases in chronic ailments and frailty The SCI state in older individuals is thought to be caused in part
that are frequently associated with age rather than to biological by a complex process called cellular senescence, which is charac-
aging itself. terized by an arrest of cell proliferation and the development of a
To address limitations associated with assessing only a few multifaceted senescence-associated secretory phenotype (SASP)53.
select inflammatory biomarkers, some researchers have employed A prominent feature of this phenotype is increased secretion of pro-
a multi-dimensional approach that involves assaying large numbers inflammatory cytokines, chemokines and other pro-inflammatory
of inflammatory markers and then combining these markers into molecules from cells53. Senescent cells expressing this phenotype
more robust indices representing heightened inflammatory activity. can in turn promote a multitude of chronic health conditions and
In one such study, researchers used principal component analysis to diseases, including insulin resistance, CVD, pulmonary arterial
identify pro- and anti-inflammatory markers and an innate immune hypertension, chronic obstructive pulmonary disorder, emphy-
response that significantly predicted risk for multiple chronic dis- sema, Alzheimer’s and Parkinson’s diseases, macular degeneration,
eases (CVD, kidney disease and diabetes), in addition to mortality51. osteoarthritis and cancer54,55.
More recently, a multi-omics approach has been applied to How senescent cells acquire the SASP is not fully understood, but
examine links between SCI and disease risk. The researchers fol- existing research points to a combination of both endogenous and
lowed 135 adults longitudinally and conducted deep molecular non-endogenous social, environmental and lifestyle risk factors.
profiling of participants’ whole-blood gene expression, termed the Among the known endogenous causes of this phenotype are DNA
transcriptome; immune proteins—for example, cytokines and che- damage, dysfunctional telomeres, epigenomic disruption, mitogenic
mokines—termed the immunome; and cell subset frequencies, such signals and oxidative stress56. The non-endogenous contributors are
as CD8+ T cell subsets, monocytes, natural killer (NK) cells, B cells thought to include chronic infections57, lifestyle-induced obesity58,
and CD4+ T cell subsets. This enabled the researchers to construct microbiome dysbiosis59, diet60, social and cultural changes61,62 and
a high-dimensional trajectory of immune aging (IMM-AGE) that environmental and industrial toxicants63. The fact that differences
described individuals’ immune functioning better than their chron- exist in the extent to which older adults exhibit SCI52,64 is thought
ological age. This new metric in turn accurately predicted all-cause to be indicative of inter-individual differences in exposure to these
mortality, establishing its potential future use for identifying at-risk and other related pro-inflammatory factors, although studies docu-
patients in clinical settings52. These types of integrative, multi-level menting within-person associations between these risk factors and
approaches to characterizing SCI are promising, but this work is SCI are limited.
still in its infancy and much more research is needed to identify Nevertheless, differences in non-communicable diseases asso-
best practices for selecting and analyzing SCI-related biomarkers in ciated with SCI are evident across cultures and countries. Most

prominently, SCI-related disease rates have increased dramatically including social stability; reduced physical trauma; access to mod-
for both older and younger individuals living in industrialized coun- ern medical technology; and improved public health measures, such
tries who follow a Western lifestyle but are relatively rare among as sanitation, quarantine policies and vaccination, all of which sig-
individuals in non-Westernized populations who adhere to diets, nificantly decrease infant mortality rates and increase average life
lifestyles and ecological niches that more closely resemble those expectancy66. However, more recently, these changes also caused
present during most of human evolution65–71. Furthermore, dietary radical shifts in diet and lifestyle, resulting in living circumstances
and lifestyle habits, as well as exposure to a variety of different pol- that are very different from the ones that shaped human physiology
lutants, can increase oxidative stress, upregulate mitogenic signaling for most of evolution. This is believed to have created an evolution-
pathways and cause genomic and epigenomic perturbations8,60,62,63 ary mismatch in humans—characterized by an increasing separa-
that can induce the SASP. Further evidence for a role of lifestyle tion from their ecological niche—and this mismatch, in turn, has
in the development of chronic inflammation comes from a study been hypothesized to be a major cause of SCI65,66,82,89,92.
of 210 healthy twins between 8 and 82 years old, which found that
non-heritable factors are the strongest contributors to differences Physical activity. Industrialization is thought to have caused a sig-
in chronic inflammation across individuals72 and that exposure to nificant overall decrease in physical activity. One study showed that,
environmental factors, which have been collectively called the expo- worldwide, 31% of individuals are considered physically inactive—
some, are the main drivers of SCI. Simply put, the exposome refers defined as not meeting the minimum international recommenda-
to a person’s lifelong exposure to physical, chemical and biological tions for regular physical activity—with levels of inactivity being
elements, starting from the prenatal period onward73. higher in high-income countries than in low-to-middle-income
countries93. In the United States, these numbers are even higher,
Chronic infections. The effect of lifelong infections caused by with approximately 50% of American adults being considered phys-
cytomegalovirus, Epstein–Barr virus, hepatitis C virus and other ically inactive94.
infectious agents on SCI and immune dysregulation remains con- Skeletal muscle is an endocrine organ that produces and releases
troversial74–78. In terms of aging, chronic infection with cytomegalo- cytokines and other small proteins, called myokines, into the blood-
virus has been associated with the so-called immune risk phenotype stream. This occurs particularly during muscle contraction and
that has been predictive of early mortality in several longitudinal can have the effect of systemically reducing inflammation95. Low
studies79. Furthermore, chronic infection with HIV causes prema- physical activity, therefore, has been found to be directly related to
ture aging of the immune system and is associated with early cardio- increased anabolic resistance96 and levels of CRP and pro-inflam-
vascular and skeletal changes57, with such effects being attributed in matory cytokine levels in healthy individuals97, as well as in breast
large part to the accumulation of senescent CD8+ T cells that pro- cancer survivors98 and patients with type 2 diabetes99. These effects
duce increased levels of pro-inflammatory mediators80. can, in turn, promote several inflammation-related pathophysi-
Although several studies have reported associations between ologic alterations, including insulin resistance, dyslipidemia, endo-
chronic infections and autoimmune diseases, certain cancers, neu- thelial dysfunction, high blood pressure and loss of muscle mass
rodegenerative diseases and CVD, chronic infections appear to (sarcopenia)100, that have been found to increase risk for a variety of
interact synergistically with environmental and genetic factors to conditions, including CVD, type 2 diabetes, NAFLD, osteoporosis,
influence these health outcomes76,77,81. Indeed, humans coevolved various types of cancer, depression, dementia and Alzheimer’s dis-
with a variety of viruses, bacteria and other microbes82, and while ease, in individuals who are chronically inactive95,100.
chronic infections appear to contribute to SCI, they are not likely Consistent with these effects, there is strong evidence for an
the primary driver. For instance, populations of hunter-gatherers association between physical inactivity and increased risk for age-
and other existing non-industrialized societies such as the Shuar related diseases and mortality. A recent meta-analysis of studies
hunter-gatherers of the Ecuadorian Amazon83,84, Tsimané for- with cohorts from Europe, the United States and the rest of the
ager-horticulturalists of Bolivia68, Hadza hunter-gatherers from world that included 1,683,693 participants found that going from
Tanzania67, subsistence agriculturalists from rural Ghana85 and tra- physically inactive to achieving the recommended 150 minutes of
ditional horticulturalists of Kitava (Papua New Guinea)86—all of moderate-intensity aerobic activity per week was associated with
whom are minimally exposed to industrialized environments but lower risk of CVD mortality by 23%, CVD incidence by 17%,
highly exposed to a variety of microbes—exhibit very low rates of and type 2 diabetes incidence by 26% during an average follow-
inflammation-related chronic disease and substantial fluctuations up period of 12.8 years101. Moreover, data from 1.44 million par-
in inflammatory markers that do not increase with age65,67,68,83,86. ticipants across several prospective cohort studies revealed that, as
compared to individuals exhibiting high levels of leisure-time phys-
Lifestyle, social and physical environment. Individuals in the ical activity (≥90th percentile), those who were physically inactive
populations mentioned above have relatively short life expectan- (≤10th percentile) had a greater risk (>20%) of developing several
cies on average, which means that some die before showing signs of cancers, including esophageal adenocarcinoma; liver, lung, kidney,
advanced aging. However, the relative absence of SCI-related health gastric cardia and endometrial cancers; and myeloid leukemia, even
problems in these populations has not been attributed to genetics after adjusting for multiple major risk factors such as adiposity and
or to having a shorter life expectancy, but rather to lifestyle fac- smoking status (except for lung cancer)102. Likewise, a meta-analysis
tors and the social and physical environments the people inhabit66. of ten studies and 23,345 older adults (70 to 80 years old) who were
Their lifestyles, for example, are characterized by higher levels of followed for 3.9–31 years found that individuals meeting the mini-
physical activity67,71,87, diets composed mainly of fresh or minimally mum international physical activity recommendations had a 40%
processed food sources66,88,89, and less exposure to environmental lower risk of Alzheimer’s disease as compared to their physically
pollutants66. In addition, individuals living in these environments inactive counterparts103.
generally have circadian rhythms that are more closely synchro- Finally, physical inactivity can increase individuals’ risk for vari-
nized with diurnal fluctuations in sunlight exposure90 and the social ous non-communicable diseases because it is linked to obesity100
stressors they experience are different from those typically present and, in particular, excessive visceral adipose tissue (VAT), which is
in industrialized environments91. a significant trigger of inflammation104–106. VAT is an active endo-
These social and environmental characteristics are believed to have crine, immunological and metabolic organ composed of various
predominated during most of hominin evolutionary history until cells (including immune cells, such as resident macrophages) that
industrialization66,82,89. Industrialization conferred many benefits, expands mostly through adipocyte hypertrophy, which can lead

to areas of hypoxia and even cell death, resulting in activation of these effects, though. For example, orally absorbed advanced gly-
hypoxia-inducible factor-1α, increased production of reactive oxy- cation and lipoxidation end-products that are formed during the
gen species, and release of DAMPs (for example, cell-free DNA). processing of foods or when foods are cooked at high tempera-
These events can induce the secretion of numerous pro-inflamma- tures and in low-humidity conditions are appetite increasing and
tory molecules, including adipokines, cytokines (for example, IL-1β, are linked to overnutrition and hence obesity and inflammation132.
IL-6, TNF-α), and chemokines (especially monocyte chemoattrac- Furthermore, high-glycemic-load foods, such as isolated sugars
tant protein-1) by adipocytes, endothelial cells and resident adipose and refined grains, which are common ingredients in most ultra-
tissue immune cells (for example, macrophages)105–108. This in turn processed foods, can cause increased oxidative stress that activates
leads to the infiltration of various immune cells in the VAT, includ- inflammatory genes133.
ing monocytes, neutrophils, dendritic cells, B cells, T cells and NK Other dietary components that are thought to influence inflam-
lymphocytes, and a reduction in T regulatory cells, thereby ampli- mation include trans fatty acids134 and dietary salt. For example, salt
fying inflammation, which can eventually become prolonged and has been shown to skew macrophages toward a pro-inflammatory
systemic in some individuals106–109. phenotype characterized by the increased differentiation of naive
Furthermore, TNF-α and other molecules can cause adipocyte CD4+ T cells into T helper (TH)-17 cells, which are highly inflam-
insulin resistance, which increases lipolysis, with the resulting matory, and decreased expression and anti-inflammatory activity of
spillover of lipids into other organs, such as the pancreas and liver, T regulatory cells135. In addition, high salt intake can cause adverse
where they can contribute to beta-cell dysfunction, hepatic insulin changes in gut microbiota composition, as exemplified by the
resistance and fatty liver106. Hence, visceral obesity accelerates aging reduced Lactobacillus population observed in animals and humans
and increases risk for cardiometabolic, neurodegenerative and fed high-salt diets135. This specific population is critical for health as
autoimmune diseases, as well as several types of cancer19,104,106,110–112. it regulates TH17 cells and enhances the integrity of the intestinal epi-
These dynamics are known to occur in adults and can promote age- thelial barrier, thus reducing systemic inflammation135. Consistent
related disease risk, but they first emerge during childhood26. The with the expected health-damaging effects of consuming foods that
childhood obesity epidemic might thus be playing a key role in pro- are high in trans fats and salt, a recent cohort study of 44,551 French
moting inflammation and age-related disease risk worldwide113. adults who were followed for a median of 7.1 years found that a 10%
increase in the proportion of ultra-processed food consumption was
Microbiome dysbiosis. Obesity may also lead to SCI through gut associated with a 14% greater risk of all-cause mortality136.
microbiome-mediated mechanisms114. For example, studies con- Several other nutritional factors can also promote inflammation
ducted in moderately obese Danish individuals without diabetes115 and potentially contribute to the development of SCI. These factors
and in severely obese French women116 found changes in gut micro- include deficiencies in micronutrients, including zinc137 and magne-
biota composition and microbial gene richness that were correlated sium138, which are caused by eating processed or refined foods that
with increased fat mass, pro-inflammatory biomarkers and insulin are low in vitamins and minerals, and having suboptimal omega-3
resistance. Furthermore, in older adults, changes in the gut microbiota levels139, which impacts the resolution phase of inflammation. Long-
seem to influence the outcome of multiple inflammatory pathways59. chain omega-3 fatty acids—especially eicosapentaenoic acid and
Obesity, which is strongly linked to changes in the gut micro- docosahexaenoic acid—modulate the expression of genes involved
biome, has also been associated with increased intestinal paracel- in metabolism and inflammation139. More importantly, they are pre-
lular permeability and endotoxemia114,117. Moreover, the latter is cursors to molecules such as resolvins, maresins and protectins that
a suspected cause of inflammation through activation of pattern are involved in the resolution of inflammation28,29. The main con-
recognition receptors, such as Toll-like receptors, in immune cells tributors to the growing worldwide incidence of low omega-3 status
and of inflammation-mediated metabolic conditions such as insulin are a low intake of fish and high intake of vegetable oils that are high
resistance118. Interestingly, serum concentrations of zonulin, a pro- in linoleic acid, which displaces omega-3 fatty acids in cell mem-
tein that increases intestinal permeability, appear to be elevated in brane phospholipids140,141. In turn, various RCTs have shown that
obese children and adults117,119, and in persons with type 2 diabe- omega-3 fatty acid supplementation reduces inflammation142–144 and
tes118, NAFLD, coronary heart disease, polycystic ovary syndrome, may thus have health-promoting effects141–144.
autoimmune diseases and cancer117. More recently, elevated serum Evidence linking diet and mortality is robust. For example, an
zonulin concentrations have been found to predict inflammation analysis of nationally representative health surveys and disease-
and physical frailty120. specific mortality statistics from the National Center for Health
More broadly, it has been hypothesized that a complex balance Statistics in the United States showed that the dietary risk factors
exists in the intestinal ecosystem that, if disrupted, can compro- associated with the greatest mortality among American adults in
mise its function and integrity and in turn cause low-grade SCI59. It 2005 were high dietary trans fatty acids, low dietary omega-3 fatty
may thus be important to identify possible triggers of dysbiosis and acids, and high dietary salt145. In addition, a recent systematic analy-
intestinal hyperpermeability, which could potentially include the sis of dietary data from 195 different countries identified poor diet
overuse of antibiotics, nonsteroidal anti-inflammatory drugs and as the main risk factor for death in 2017, with excessive sodium
proton-pump inhibitors121,122; lack of microbial exposure induced intake being responsible for more than half of diet-related deaths146.
by excessive hygiene and reduced contact with animals and natural Finally, when combined with low physical activity, consuming
soils, which is a very recent phenomenon in human evolutionary hyperpalatable processed foods that are high in fat, sugar, salt and
history82,123; and diet123 (see below). flavor additives147 can cause major changes in cell metabolism and
lead to the increased production (and defective disposal) of dys-
Diet. The typical diet that has become widely adopted in many functional organelles such as mitochondria, as well as to misplaced,
countries over the past 40 years is relatively low in fruits, vegetables misfolded and oxidized endogenous molecules30,60,148. These altered
and other fiber- and prebiotic-rich foods66,123–125 and high in refined molecules, which increase with age19,30, can be recognized as DAMPs
grains124, alcohol126 and ultra-processed foods125, particularly those by innate immune cells, which in turn activate the inflammasome
containing emulsifiers127. These dietary factors can alter the gut machinery, amplify the inflammatory response1,30,60 and contribute
microbiota composition and function123,127–130 and are linked to to a biological state that has been called “inflammaging,” defined as
increased intestinal permeability129–131 and epigenetic changes in the the “the long-term result of the chronic physiological stimulation of
immune system129 that ultimately cause low-grade endotoxemia and the innate immune system” that occurs in later life30. As proposed,
SCI129–131. The influence of diet on inflammation is not confined to inflammaging involves changes in numerous organ systems, such

as the brain, gut, liver, kidney, adipose tissue and muscle19, and it is later in life, which in turn promote SCI in adulthood8,26,27,168,169.
driven by a variety of molecular-age-related mechanisms that have Childhood obesity, for instance, is strongly associated with major
been called the “Seven Pillars of Aging”55—namely, adaptation to changes in adipose tissue and metabolic dysfunction that cause
stress, epigenetics, inflammation, macromolecular damage, metab- metabolism-related-SCI, or so-called metainflammation26. Because
olism, proteostasis and stem cells and regeneration. obese children often become obese adolescents and adults26, the risk
of developing a pro-inflammatory phenotype also frequently per-
Social and cultural changes. In addition to physical inactivity and sists into adulthood among individuals who were obese as children.
diet, the industrial revolution and modern era have ushered in Another example of SCI being influenced by early life circum-
changes in social interactions and sleep quality59,91 that can promote stances comes from epidemiologic studies showing that greater
SCI149,150 and insulin resistance151, in turn increasing risk for obe- microbial exposure in infancy is associated with reduced risk of
sity, type 2 diabetes, CVD and all-cause mortality150–154. Moreover, chronic inflammation in adulthood8,168, as predicted by the hygiene,
psychological stressors that are persistently present in some con- or ‘old friends’, hypothesis82. Additionally, there is evidence that
temporary work environments, such as those characterized by high exposure to psychological stress early in life—for example, in the
job demand and low control, can cause physiologic changes155 that form of abuse, neglect, maltreatment, bullying or living in a low
disrupt the ability for glucocorticoids to effectively down-regulate socioeconomic environment—can heighten neural responses to
inflammatory activity due to decreased sensitivity caused by chronic threat that can upregulate inflammatory activity170, alter immuno-
elevation in cortisol, leading in turn to SCI and poor health156. competence and lead to SCI throughout the lifecycle27,169.
Another core feature of modern society that has occurred very Further back in the developmental trajectory are data show-
recently in human evolutionary history is increased exposure ing that the immune system is programmed during the prenatal
to artificial light, especially the blue spectrum, at atypical bio- period171 and is affected by epigenetic changes induced by mater-
logic times157–159. Exposure to blue light, especially after sundown, nal environmental exposures (for example, infectious agents, diet,
increases arousal and alertness at night and thus causes circadian psychological stress and xenobiotics) during intrauterine life and
rhythm disruption158,159, which in turn promotes inflammation160, even before conception, when paternal factors may also have an
and is a risk for multiple inflammation-related diseases157,159. As epigenetic effect26,128,171. Together, these effects create the potential
an example, night-shift work has been found to increase risk for for the intergenerational transmission of risk for SCI. In this model
the metabolic syndrome and is suspected of being a causal factor (Fig. 2), SCI and disease risk are hypothesized to be perpetuated
in obesity, type 2 diabetes and CVD, as well as in breast, ovarian, transgenerationally. In short, maternal inflammation during preg-
prostate, colorectal and pancreatic cancer157. nancy172,173 is believed to pass an inflammatory ‘code’ through epi-
genetic modifications to the offspring, who will exhibit elevated risk
Environmental and industrial toxicants. The rapid rise in urban- for SCI in childhood and adulthood and therefore be more likely
ization over the past 200 years8 brought with it an unprecedented to suffer from a wide variety of inflammation-related health prob-
increase in humans’ exposure to various xenobiotics, including air lems, including obesity7, CVD7, cancer174 and neurological illness175,
pollutants, hazardous waste products and industrial chemicals that among others, only to again pass this risk on to their own offspring.
promote SCI8,161. Each year, an estimated 2,000 new chemicals are
introduced into items that individuals use or ingest daily, including Chronic inflammation and the immune response to acute
foods, personal care products, prescription drugs, household clean- challenges
ers and lawn care products (see https://ntp.niehs.nih.gov). The con- Despite the observation that SCI generally increases with age, a
comitant increase in the estimated contribution of environmental majority of older adults experience a down-regulation of compo-
chemicals to human disease burden162 has prompted a shift toward nents of the immune response that leads to an increased suscepti-
data generation using high-throughput screening to investigate the bility to viral infections and weakened responses to vaccines. This
effect of industrial toxicants on cellular pathways, which has been apparent paradox (Fig. 3) can be explained by several mechanisms.
supported by initiatives like the US Federal Tox21 Program, and Specifically, elevated SCI can lead to a basal low-grade consti-
toward the adoption of translational systems-toxicology approaches tutive activation of various signaling pathways, such as the Janus
for integrating diverse data streams to better understand how kinase/signal transducers and activators of transcription (JAK–
chemicals affect human health and disease outcomes163. The Tox21 STAT) system in leukocytes, which results in a weakened acute
Program has tested more than 9,000 chemicals using more than response to multiple stimuli in immune cells from older adults
1,600 assays and has demonstrated that numerous chemicals to with chronic inflammation due to reduced fold-increase in the
which people are commonly exposed greatly alter molecular signal- levels of phosphorylation of these proteins after cell stimulation22.
ing pathways that underlie inflammation and inflammation-related Elevated SCI has also been shown to predict hyporesponsiveness to
disease risk164. These chemicals include phthalates, per- and polyflu- the hepatitis B vaccine in humans24. Additionally, there is evidence
oroalkyl substances, bisphenols, polycyclic aromatic hydrocarbons that certain inflammatory biomarkers, such as CRP, are inversely
and flame retardants165. correlated with older adults’ response to other vaccines, such as the
These compounds and others promote inflammatory activity via herpes zoster vaccine23. Interestingly, this also seems to be true for
multiple mechanisms. For example, they can be cytotoxic8,162, cause younger individuals. Among adolescents, for example, those who
oxidative stress or act as endocrine disruptors, starting in utero8. respond well to typhoid vaccination have been found to exhibit
These chemicals are thus suspected of playing a causal role in hor- lower concentrations of CRP than non-responders in adulthood25.
mone-dependent cancers, metabolic syndrome, type 2 diabetes, In sum, this research helps to explain the pro-inflammatory/anti-
hypertension, CVD, allergy and asthma, and autoimmune and neu- viral skewing that occurs as individuals age. This work also sug-
rodegenerative diseases8,162,166. Tobacco smoking, which remains a gests that exposure to an inflammatory environment early in life
worldwide health problem, is yet another source of xenobiotics that is an important determinant of multiple aspects of an individual’s
has been associated with a variety of inflammation-related diseases167. immuno-phenotype in adulthood.
Developmental origins of systemic chronic inflammation Future directions

The origins of SCI can also be viewed from a developmental per- Considered together, this body of research provides converging
spective. For example, it is well established that childhood cir- evidence that SCI is associated with increased risk for developing a
cumstances significantly impact metabolic and immune responses variety of chronic diseases that dominate present-day morbidity and

?, ?, ?
Onset
Chronic condition
Proinflammatory Extracellular
environment
Baseline pSTAT
Fold-change Intracellular
response
Cellular output
(reduced or altered)
Fig. 2 | The maternal exposome and low-grade systemic chronic
inflammation. Maternal lifestyle and environmental exposures—
collectively referred to as the exposome—include diet, physical activity, Immune system
psychological stress and exposure to various xenobiotics, such as function and physiology
pollutants and smoking during intrauterine life. These factors in turn
can influence the programming of the immune system of the offspring, Unhealthy
potentially leading to a more pro-inflammatory phenotype later in life. cardiovascular aging
Relevant factors, including environmental factors such as poor access to
healthy food, housing insecurity, psychological stress and polluted air, lead Time/age
to a mother giving birth to a fetus with epigenetic marks that increase the
Fig. 3 | Inflammatory model of immunosenescence and chronic disease.
child’s risk for obesity, low-grade SCI and its associated consequences in
This proposed model associates elevated baseline phosphorylated
adolescence and adulthood.
signaling proteins (for example, phosphorylated STAT (pSTAT) levels)
with cellular unresponsiveness and chronically elevated inflammatory
mortality worldwide and that cause enormous amounts of human activity. The model involves an elevation of baseline pSTAT levels and
suffering. At the same time, there are several key avenues that could its association with hallmark phenomenon of immunosenescence, an
be pursued to help strengthen this work and translate this research increased pro-inflammatory environment, unresponsive cells and a clinical
into effective strategies for improving human health. impact on immune response. (Adapted with permission from ref. 22,
First, there is a clear need for additional studies that collect data Elsevier.)
on multiple factors affecting SCI to form a more comprehensive pic-
ture of how exposures and experiences identified at different levels
of analysis combine to affect SCI and inflammation-related disease collected inflammatory biomarker data under basal conditions in
risk. Second, the field sorely needs robust integrative biomarkers of which the immune system is not challenged. This is a sensible
SCI that go beyond combining a few canonical biomarkers of acute starting place, but such research does not provide any informa-
inflammation. Existing biomarkers, which have primarily included tion regarding biological reactivity or recovery (for example, from
CRP, IL-1β, IL-6 and TNF-α, have been useful for demonstrating infection or psychological or physiological stress), which may ulti-
that inflammatory activity is related to disease and mortality risk, mately be most useful for understanding individual differences in
but these markers provide only limited mechanistic information inflammation-related disease risk3,179. Finally, although many of the
(given the enormous complexity of the inflammatory response) and SCI-promoting factors that we have described herein are at least
they do not address anti-inflammatory regulatory pathways that partly modifiable—including physical inactivity, poor diet, night-
may also be relevant for influencing inflammation-related disease time blue light exposure, tobacco smoking, environmental and
risk. Future research should thus focus on additional biomarkers industrial toxicants exposure and psychological stress—the num-
that have been found to have substantial variability across indi- ber of studies that have successfully targeted these risk factors and
viduals, such as CD8+ T cell subsets, monocytes, NK cells, B cells shown corresponding reductions in SCI levels is limited. This has
and CD4+ T cell subsets176. This work should also include molec- occurred despite the fact that the association between inflammation
ular, transcriptional and proteomic markers of SCI, which have and chronic disease is now widely recognized and that healthcare
only been examined in limited ways to date177. Constructing bio- systems are buckling due to the enormous cost of treating a world-
markers that integrate information from a variety of different data wide population that is heavily burdened by SCI-related chronic
sources and levels of analysis to represent inflammatory activity and health problems. Therefore, the time to start seriously studying how
immune regulation and dysregulation would be particularly useful, to prevent and treat SCI-related disease risk in both children and
as would applying multi-omics approaches, computational model- adults is now.
ing and artificial intelligence to study how SCI-related mechanisms In conclusion, we have a long way to go before we fully under-
both change and predict changes in clinical status within individu- stand the role that SCI plays in disease risk, biological aging and
als over the life span178. mortality. For example, no study to date has assessed the entire
Third, given the difficulty associated with experimentally human exposome over the entire developmental trajectory, start-
manipulating factors such as diet, sleep and stress levels that ing in utero (for example, by measuring maternal exposures, type
affect inflammation, a majority of studies conducted thus far have of delivery and early-life nutrition) and continuing into adulthood

(for example, by assessing social and cultural processes, xenobiotic 24. Fourati, S. et al. Pre-vaccination inflammation and B-cell signalling predict
exposures, individual lifestyle habits, lifelong antibiotic use, vac- age-related hyporesponse to hepatitis B vaccination. Nat. Commun. 7,
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Psychopharmacology (Berl.) 236, 3063–3079 (2019). © Springer Nature America, Inc. 2019

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Chronic inflammation in the etiology of disease

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