Chronic inflammation in the etiology of disease across the life span
Open accessAbstract
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 diagnosis, prevention and treatment of SCI.
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- Premisecitation
These behavioral changes can be critical for survival during physical injury and microbial threat.
“These behavioral changes can be critical for survival during times of physical injury and microbial threat14.”
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Depending on the inflammatory response, metabolic and neuroendocrine changes can occur to conserve energy and direct nutrients to the activated immune system.
“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 system9–12.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [9] Kotas, M. E. & Medzhitov, R. Homeostasis, inflammation, and disease susceptibility. Cell 160, 816–827 (2015). source
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A normal inflammatory response is temporally restricted, upregulating inflammatory activity when a threat is present and resolving after the threat passes.
“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.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [9] Kotas, M. E. & Medzhitov, R. Homeostasis, inflammation, and disease susceptibility. Cell 160, 816–827 (2015). source
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- Interpretationcitation
Systemic chronic inflammation during pregnancy and childhood can elevate the risk of non-communicable diseases across the life span.
“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.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [7] Fleming, T. P. et al. Origins of lifetime health around the time of conception: causes and consequences. Lancet 391, 1842–1852 (2018). source
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Systemic chronic inflammation is typically triggered by damage-associated molecular patterns without an acute infectious insult or pathogen-associated molecular pattern activation.
“In contrast, SCI is typically triggered by DAMPs in the absence of an acute infectious insult or activation of PAMPs30–32.”
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Systemic chronic inflammation often increases with age, as older individuals have higher circulating cytokines, chemokines, acute phase proteins, and inflammatory gene expression.
“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.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [1] Furman, D. et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat. Med. 23, 174–184 (2017). source
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The empirical evidence that inflammation contributes to disease onset or progression is strongest for metabolic syndrome, type 2 diabetes, and cardiovascular disease.
“Empirical evidence that inflammation plays a role in disease onset or progression is strongest for metabolic syndrome, type 2 diabetes and CVD.”
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In a meta-analysis of more than 160,000 people across 54 prospective studies, higher circulating CRP was associated with increased risk of coronary heart disease and cardiovascular disease mortality.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [41] Emerging Risk Factors Collaboration. et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 375, 132–140 (2010). source
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High-sensitivity C-reactive protein predicts cardiovascular events in men and women.
“the inflammatory biomarker high-sensitivity C-reactive protein (CRP) is a predictor of cardiovascular events in men and women40.”
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A principal component analysis-derived index of pro- and anti-inflammatory markers and innate immune response significantly predicted risk for cardiovascular disease, kidney disease, diabetes, and mortality.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [51] Morrisette-Thomas, V. et al. Inflamm-aging does not simply reflect increases in pro-inflammatory markers. Mech. Ageing Dev. 139, 49–57 (2014). source
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The risk of developing Alzheimer's disease was significantly lower among patients with rheumatoid arthritis treated with the TNF-α inhibitor etanercept.
“The risk for developing Alzheimer’s disease was also significantly lower among patients with rheumatoid arthritis treated with the TNF-α inhibitor etanercept43.”
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Canakinumab-treated patients had a lower likelihood of unstable angina leading to urgent revascularization.
“canakinumab-treated patients also exhibited a lower likelihood of unstable angina leading to urgent revascularization44.”
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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.
“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.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [48] Ahluwalia, N. et al. Cytokine production by stimulated mononuclear cells did not change with aging in apparently healthy, well-nourished women. Mech. Ageing Dev. 122, 1269–1279 (2001). source
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In monocytes from ambulatory individuals, levels of IL-6 and IL-1Ra, but not IL-1β or TNF-α, increased with age.
“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.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47] Roubenoff, R. et al. Monocyte cytokine production in an elderly population: effect of age and inflammation. J. Gerontol. A Biol. Sci. Med. Sci. 53, M20–M26 (1998). source
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Known endogenous causes of the senescence-associated secretory phenotype include DNA damage, dysfunctional telomeres, epigenomic disruption, mitogenic signals, and oxidative stress.
“Among the known endogenous causes of this phenotype are DNA damage, dysfunctional telomeres, epigenomic disruption, mitogenic signals and oxidative stress56.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [56] Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013). source
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- Interpretationcitation
Systemic chronic inflammation in older individuals is thought to be caused in part by cellular senescence and its senescence-associated secretory phenotype.
“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.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [53] Coppé, J.-P., Desprez, P.-Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010). source
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Senescent cells expressing the senescence-associated secretory phenotype promote multiple chronic conditions, including insulin resistance, cardiovascular disease, pulmonary arterial hypertension, chronic obstructive pulmonary disorder, emphysema, Alzheimer's and Parkinson's diseases, macular degeneration, osteoarthritis, and cancer.
“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 cancer54,55.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [54] Zhu, Y., Armstrong, J. L., Tchkonia, T. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr. Opin. Clin. Nutr. Metab. Care 17, 324–328 (2014). source
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Chronic infections interact synergistically with environmental and genetic factors to influence autoimmune diseases, certain cancers, neurodegenerative diseases, and cardiovascular disease.
“chronic infections appear to interact synergistically with environmental and genetic factors to influence these health outcomes76,77,81.”
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Chronic cytomegalovirus infection is associated with an immune risk phenotype that has predicted early mortality in several longitudinal studies.
“chronic infection with cytomegalovirus has been associated with the so-called immune risk phenotype that has been predictive of early mortality in several longitudinal studies79.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [79] Pawelec, G. et al. Human immunosenescence: is it infectious? Immunol. Rev. 205, 257–268 (2005). source
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- Interpretationcitation
The relative absence of systemic chronic inflammation-related health problems in non-industrialized populations is attributed to lifestyle factors and the social and physical environments they inhabit, not to genetics or shorter life expectancy.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [66] Carrera-Bastos, P., Fontes-Villalba, M., O’Keefe, J. H., Lindeberg, S. & Cordain, L. The western diet and lifestyle and diseases of civilization. Res. Rep. Clin. Cardiol. 2, 15–35 (2011).
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Low physical activity is directly related to increased anabolic resistance and levels of CRP and pro-inflammatory cytokines in healthy individuals, breast cancer survivors, and patients with type 2 diabetes.
“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.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [96] Breen, L. et al. Two weeks of reduced activity decreases leg lean mass and induces ‘anabolic resistance’ of myofibrillar protein synthesis in healthy elderly. J. Clin. Endocrinol. Metab. 98, 2604–2612 (2013). source
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These social and environmental characteristics are believed to have predominated during most of hominin evolutionary history until industrialization.
“These social and environmental characteristics are believed to have predominated during most of hominin evolutionary history until industrialization66,82,89.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [66] Carrera-Bastos, P., Fontes-Villalba, M., O’Keefe, J. H., Lindeberg, S. & Cordain, L. The western diet and lifestyle and diseases of civilization. Res. Rep. Clin. Cardiol. 2, 15–35 (2011).
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A meta-analysis of ten studies and 23,345 older adults found that meeting minimum international physical activity recommendations was associated with a 40% lower risk of Alzheimer's disease compared with physically inactive counterparts.
“a meta-analysis of ten studies and 23,345 older adults (70 to 80 years old) who were followed for 3.9–31 years found that individuals meeting the minimum international physical activity recommendations had a 40% lower risk of Alzheimer’s disease as compared to their physically inactive counterparts103.”
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The childhood obesity epidemic might play a key role in promoting inflammation and age-related disease risk worldwide.
“The childhood obesity epidemic might thus be playing a key role in promoting inflammation and age-related disease risk worldwide113.”
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In older adults, changes in the gut microbiota seem to influence the outcome of multiple inflammatory pathways.
“in older adults, changes in the gut microbiota seem to influence the outcome of multiple inflammatory pathways59.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [59] Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 159, 1–15 (2018).
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- Interpretationcitation
Obesity may lead to systemic chronic inflammation through gut microbiome-mediated mechanisms.
“Obesity may also lead to SCI through gut microbiome-mediated mechanisms114.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [114] Cani, P. D. & Jordan, B. F. Gut microbiota-mediated inflammation in obesity: a link with gastrointestinal cancer. Nat. Rev. Gastroenterol. Hepatol. 15, 671–682 (2018). source
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Elevated serum zonulin concentrations predict inflammation and physical frailty.
“More recently, elevated serum zonulin concentrations have been found to predict inflammation and physical frailty120.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [120] Qi, Y. et al. Intestinal permeability biomarker zonulin is elevated in healthy aging. J. Am. Med. Direc. Assoc. 18, 810.e1–810.e4 (2017). source
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Studies in moderately obese Danish individuals without diabetes and severely obese French women found changes in gut microbiota composition and microbial gene richness that correlated with increased fat mass, pro-inflammatory biomarkers, and insulin resistance.
“studies conducted in moderately obese Danish individuals without diabetes115 and in severely obese French women116 found changes in gut microbiota composition and microbial gene richness that were correlated with increased fat mass, pro-inflammatory biomarkers and insulin resistance.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [115] Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013). source
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High-glycemic-load foods such as isolated sugars and refined grains can cause increased oxidative stress that activates inflammatory genes.
“high-glycemic-load foods, such as isolated sugars and refined grains, which are common ingredients in most ultra-processed foods, can cause increased oxidative stress that activates inflammatory genes133.”
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High salt intake produces harmful changes in gut microbiota composition, such as a smaller Lactobacillus population, in both animals and humans.
“high salt intake can cause adverse changes in gut microbiota composition, as exemplified by the reduced Lactobacillus population observed in animals and humans fed high-salt diets135”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [135] Muller, D. N., Wilck, N., Haase, S., Kleinewietfeld, M. & Linker, R. A. Sodium in the microenvironment regulates immune responses and tissue homeostasis. Nat. Rev. Immunol. 19, 243–254 (2019). source
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In a cohort of 44,551 French adults followed for a median of 7.1 years, a 10% increase in the share of ultra-processed food consumed was linked to a 14% higher risk of death from any cause.
“a recent cohort study of 44,551 French 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 associated with a 14% greater risk of all-cause mortality136”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [136] Schnabel, L. et al. Association between ultraprocessed food consumption and risk of mortality among middle-aged adults in France. JAMA Intern. Med. 179, 490–498 (2019). source
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Long-chain omega-3 fatty acids, especially EPA and DHA, influence the activity of genes related to metabolism and inflammation.
“Longchain omega-3 fatty acids—especially eicosapentaenoic acid and docosahexaenoic acid—modulate the expression of genes involved in metabolism and inflammation139”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [139] Calder, P. C. Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochem. Soc. Trans. 45, 1105–1115 (2017). source
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An analysis of US national health surveys and disease-specific mortality data found that the dietary risk factors linked to the most deaths among American adults in 2005 were high trans fatty acid intake, low omega-3 intake, and high salt intake.
“an analysis of nationally representative health surveys and diseasespecific mortality statistics from the National Center for Health Statistics in the United States showed that the dietary risk factors associated with the greatest mortality among American adults in 2005 were high dietary trans fatty acids, low dietary omega-3 fatty acids, and high dietary salt145”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [145] Danaei, G. et al. The preventable causes of death in the United States: comparative risk assessment of dietary, lifestyle, and metabolic risk factors. PLoS Med. 6, e1000058 (2009). source
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Suboptimal omega-3 levels affect the resolution phase of inflammation.
“having suboptimal omega-3 levels139, which impacts the resolution phase of inflammation”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [139] Calder, P. C. Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochem. Soc. Trans. 45, 1105–1115 (2017). source
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Inflammaging affects multiple organ systems, among them the brain, intestines, liver, kidneys, fat tissue and muscle.
“inflammaging involves changes in numerous organ systems, such as the brain, gut, liver, kidney, adipose tissue and muscle19”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018). source
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The rapid rise in urbanization over the past 200 years brought an unprecedented increase in human exposure to xenobiotics, such as air pollutants, hazardous waste and industrial chemicals that drive SCI.
“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”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [8] Renz, H. et al. An exposome perspective: early-life events and immune development in a changing world. J. Allergy Clin. Immunol. 140, 24–40 (2017). source
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- cites [161] Jiang, C. et al. Dynamic human environmental exposome revealed by longitudinal personal monitoring. Cell 175, 277–291.e31 (2018). source
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These chemicals include bisphenols, flame retardants, phthalates, polycyclic aromatic hydrocarbons, and per- and polyfluoroalkyl substances.
“These chemicals include phthalates, per- and polyfluoroalkyl substances, bisphenols, polycyclic aromatic hydrocarbons and flame retardants165”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [165] Thompson, P. A. et al. Environmental immune disruptors, inflammation and cancer risk. Carcinogenesis 36, S232–S253 (2015). source
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Childhood obesity is closely linked to substantial alterations in fat tissue and metabolic dysfunction that produce metabolism-related SCI, or metainflammation.
“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”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Singer, K. & Lumeng, C. N. The initiation of metabolic inflammation in childhood obesity. J. Clin. Invest. 127, 65–73 (2017). source
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Childhood conditions have a major influence on later metabolic and immune responses, which then drive SCI in adulthood.
“childhood circumstances significantly impact metabolic and immune responses later in life, which in turn promote SCI in adulthood8,26,27,168,169”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [8] Renz, H. et al. An exposome perspective: early-life events and immune development in a changing world. J. Allergy Clin. Immunol. 140, 24–40 (2017). source
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- cites [26] Singer, K. & Lumeng, C. N. The initiation of metabolic inflammation in childhood obesity. J. Clin. Invest. 127, 65–73 (2017). source
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- cites [27] Olvera Alvarez, H. A., Kubzansky, L. D., Campen, M. J. & Slavich, G. M. Early life stress, air pollution, inflammation, and disease: an integrative review and immunologic model of social-environmental adversity and lifespan health. Neurosci. Biobehav. Rev. 92, 226–242 (2018). source
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- cites [168] McDade, T. W., Rutherford, J., Adair, L. & Kuzawa, C. W. Early origins of inflammation: microbial exposures in infancy predict lower levels of C-reactive protein in adulthood. Proc. Biol. Sci. 277, 1129–1137 (2010). source
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Tobacco smoking is associated with a variety of inflammation-related diseases.
“Tobacco smoking, which remains a worldwide health problem, is yet another source of xenobiotics that has been associated with a variety of inflammation-related diseases167”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [167] GBD 2015 Tobacco Collaborators. Smoking prevalence and attributable disease burden in 195 countries and territories, 1990-2015: a systematic analysis from the Global Burden of Disease Study 2015. Lancet 389, 1885–1906 (2017). source
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More microbial exposure during infancy is linked to a lower chance of chronic inflammation later in adulthood, as the hygiene or 'old friends' hypothesis predicts.
“greater microbial exposure in infancy is associated with reduced risk of chronic inflammation in adulthood8,168, as predicted by the hygiene, or ‘old friends’, hypothesis82”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [8] Renz, H. et al. An exposome perspective: early-life events and immune development in a changing world. J. Allergy Clin. Immunol. 140, 24–40 (2017). source
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- cites [168] McDade, T. W., Rutherford, J., Adair, L. & Kuzawa, C. W. Early origins of inflammation: microbial exposures in infancy predict lower levels of C-reactive protein in adulthood. Proc. Biol. Sci. 277, 1129–1137 (2010). source
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- cites [82] Rook, G., Bäckhed, F., Levin, B. R., McFall-Ngai, M. J. & McLean, A. R. Evolution, human-microbe interactions, and life history plasticity. Lancet 390, 521–530 (2017). source
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- Interpretationreasoning
SCI is linked to a higher chance of developing many chronic diseases that are the main causes of illness and death today.
“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.”
Quote in the paperSubstantial claim - Interpretationreasoning
Early-life exposure to inflammation appears to shape several features of a person's immune phenotype in adulthood.
“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.”
Quote in the paperSubstantial claim - Premisecitation
Certain inflammatory biomarkers, such as CRP, are inversely correlated with older adults' response to herpes zoster vaccine.
“certain inflammatory biomarkers, such as CRP, are inversely correlated with older adults’ response to other vaccines, such as the herpes zoster vaccine23”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] Verschoor, C. P. et al. Serum C-reactive protein and congestive heart failure as significant predictors of herpes zoster vaccine response in elderly nursing home residents. J. Infect. Dis. 216, 191–197 (2017). source
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- Interpretationreasoning
These effects create the potential for intergenerational transmission of risk for SCI.
“Together, these effects create the potential for the intergenerational transmission of risk for SCI.”
Quote in the paperSubstantial claim - Interpretationreasoning
This research helps explain the pro-inflammatory/antiviral skewing that occurs as individuals age.
“In sum, this research helps to explain the pro-inflammatory/antiviral skewing that occurs as individuals age.”
Quote in the paperSubstantial claim- Rests on an assumption: A majority of older adults experience down-regulation of immune response components, leading to increased susceptibility to viral infections and weakened vaccine responses.
- Premisecitation
Among adolescents, good responders to typhoid vaccination have lower CRP levels in adulthood than non-responders.
“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”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] McDade, T. W., Adair, L., Feranil, A. B. & Kuzawa, C. Positive antibody response to vaccination in adolescence predicts lower C-reactive protein concentration in young adulthood in the Philippines. Am. J. Hum. Biol. 23, 313–318 (2011). source
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- Interpretationreasoning
In principle, SCI can be modified to a large degree.
“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.”
Quote in the paperNot a substantial claim- Rests on an assumption: No study to date has assessed the entire human exposome over the entire developmental trajectory.
- Rests on an assumption: Only a few studies have investigated how modifying SCI-related processes may benefit human health or longevity.
- Premisecitation
Elevated SCI predicts hyporesponsiveness to hepatitis B vaccine in humans.
“Elevated SCI has also been shown to predict hyporesponsiveness to the hepatitis B vaccine in humans24”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Fourati, S. et al. Pre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination. Nat. Commun. 7, 10369 (2016). source
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- Premisecitation
Elevated SCI can produce low-grade continuous activation of pathways like JAK-STAT in leukocytes, which weakens the acute response of immune cells from older adults with chronic inflammation to various stimuli, because phosphorylation of these proteins increases less after stimulation.
“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”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Shen-Orr, S. S. et al. Defective signaling in the JAK-STAT pathway tracks with chronic inflammation and cardiovascular risk in aging humans. Cell Syst. 3, 374–384.e4 (2016). source
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- May combine two claims. 65
- Classified as probably not a substantial claim. 8
- The quote only partly states this claim. 2
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PremisecitationThe risk of developing chronic inflammation can be traced to early development, and its effects persist across the life span to influence adult health and mortality risk.
“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.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [6] Miller, G. E., Chen, E. & Parker, K. J. Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Psychol. Bull. 137, 959–997 (2011). source
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- cites [7] Fleming, T. P. et al. Origins of lifetime health around the time of conception: causes and consequences. Lancet 391, 1842–1852 (2018). source
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- cites [8] Renz, H. et al. An exposome perspective: early-life events and immune development in a changing world. J. Allergy Clin. Immunol. 140, 24–40 (2017). source
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InterpretationreasoningSocial, environmental, and lifestyle factors can promote systemic chronic inflammation, which can then contribute to multiple non-communicable diseases.
“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”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationInflammation is an evolutionarily conserved process that activates immune and non-immune cells to protect the host from pathogens and promote tissue repair.
“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.”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationChronic inflammatory diseases are the most significant cause of death globally, with over half of all deaths attributable to inflammation-related diseases.
“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”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1736–1788 (2018). source
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PremisecitationInflammation produces sickness behaviors such as sadness, anhedonia, fatigue, reduced libido and food intake, altered sleep, social withdrawal, increased blood pressure, insulin resistance, and dyslipidemia.
“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 dyslipidemia10,13.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [10] Straub, R. H., Cutolo, M., Buttgereit, F. & Pongratz, G. Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J. Intern. Med. 267, 543–560 (2010). source
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- cites [13] Straub, R. H. The brain and immune system prompt energy shortage in chronic inflammation and ageing. Nat. Rev. Rheumatol. 13, 743–751 (2017). source
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InterpretationcitationA shift from short-lived to long-lived inflammation can break immune tolerance and alter tissues, organs, and cellular physiology, raising the risk of non-communicable diseases in both young and older people.
“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.”
Quote in the paperSubstantial claim0 of 10 sources checked- cites [1] Furman, D. et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat. Med. 23, 174–184 (2017). source
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- cites [9] Kotas, M. E. & Medzhitov, R. Homeostasis, inflammation, and disease susceptibility. Cell 160, 816–827 (2015). source
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- cites [10] Straub, R. H., Cutolo, M., Buttgereit, F. & Pongratz, G. Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J. Intern. Med. 267, 543–560 (2010). source
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- cites [11] Straub, R. H., Cutolo, M. & Pacifici, R. Evolutionary medicine and bone loss in chronic inflammatory diseases—a theory of inflammation-related osteopenia. Semin. Arthritis Rheum. 45, 220–228 (2015). source
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- cites [15] Fullerton, J. N. & Gilroy, D. W. Resolution of inflammation: a new therapeutic frontier. Nat. Rev. Drug Discov. 15, 551–567 (2016). source
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- cites [17] Taniguchi, K. & Karin, M. NF-κB, inflammation, immunity and cancer: coming of age. Nat. Rev. Immunol. 18, 309–324 (2018). source
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- cites [18] Gisterå, A. & Hansson, G. K. The immunology of atherosclerosis. Nat Rev. Nephrol. 13, 368–380 (2017). source
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- cites [19] Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018). source
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- cites [20] Heneka, M. T., Kummer, M. P. & Latz, E. Innate immune activation in neurodegenerative disease. Nat. Rev. Immunol. 14, 463–477 (2014). source
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- cites [21] Miller, A. H. & Raison, C. L. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat. Rev. Immunol. 16, 22–34 (2016). source
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May combine two claims.
InterpretationcitationCertain social, psychological, environmental, and biological factors prevent resolution of acute inflammation and promote low-grade sterile systemic chronic inflammation.
“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)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [13] Straub, R. H. The brain and immune system prompt energy shortage in chronic inflammation and ageing. Nat. Rev. Rheumatol. 13, 743–751 (2017). source
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- cites [16] Calder, P. C. et al. A consideration of biomarkers to be used for evaluation of inflammation in human nutritional studies. Br. J. Nutr. 109, S1–S34 (2013). source
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May combine two claims.
InterpretationcitationSystemic chronic inflammation can impair normal immune function, increasing susceptibility to infections and tumors and reducing vaccine response.
“SCI can also impair normal immune function, leading to increased susceptibility to infections and tumors and a poor response to vaccines22–25.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [22] Shen-Orr, S. S. et al. Defective signaling in the JAK-STAT pathway tracks with chronic inflammation and cardiovascular risk in aging humans. Cell Syst. 3, 374–384.e4 (2016). source
Not checked in the free run.
- cites [23] Verschoor, C. P. et al. Serum C-reactive protein and congestive heart failure as significant predictors of herpes zoster vaccine response in elderly nursing home residents. J. Infect. Dis. 216, 191–197 (2017). source
Not checked in the free run.
- cites [24] Fourati, S. et al. Pre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination. Nat. Commun. 7, 10369 (2016). source
Not checked in the free run.
- cites [25] McDade, T. W., Adair, L., Feranil, A. B. & Kuzawa, C. Positive antibody response to vaccination in adolescence predicts lower C-reactive protein concentration in young adulthood in the Philippines. Am. J. Hum. Biol. 23, 313–318 (2011). source
Not checked in the free run.
May combine two claims.
InterpretationcitationSystemic chronic inflammation is low-grade and persistent and causes collateral damage to tissues and organs over time, including oxidative stress.
“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 stress1,4,9,19.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [1] Furman, D. et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat. Med. 23, 174–184 (2017). source
Not checked in the free run.
- cites [4] Bennett, J. M., Reeves, G., Billman, G. E. & Sturmberg, J. P. Inflammation–nature’s way to efficiently respond to all types of challenges: implications for understanding and managing “the epidemic” of chronic diseases. Front. Med. 5, 316 (2018). source
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- cites [9] Kotas, M. E. & Medzhitov, R. Homeostasis, inflammation, and disease susceptibility. Cell 160, 816–827 (2015). source
Not checked in the free run.
- cites [19] Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018). source
Not checked in the free run.
May combine two claims.
PremisecitationPatients with autoimmune diseases characterized by systemic inflammation have insulin resistance, dyslipidemia, hypertension, and higher rates of metabolic syndrome, type 2 diabetes, and cardiovascular disease.
“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”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [10] Straub, R. H., Cutolo, M., Buttgereit, F. & Pongratz, G. Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J. Intern. Med. 267, 543–560 (2010). source
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- cites [12] Straub, R. H. & Schradin, C. Chronic inflammatory systemic diseases: an evolutionary trade-off between acutely beneficial but chronically harmful programs. Evol. Med. Public Health 2016, 37–51 (2016).
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- cites [37] Zhang, J. et al. The risk of metabolic syndrome in patients with rheumatoid arthritis: a meta-analysis of observational studies. PLoS One 8, e78151 (2013). source
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- cites [38] Armstrong, A. W., Harskamp, C. T. & Armstrong, E. J. Psoriasis and the risk of diabetes mellitus: a systematic review and meta-analysis. JAMA Dermatol. 149, 84–91 (2013). source
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- cites [39] Dregan, A., Charlton, J., Chowienczyk, P. & Gulliford, M. C. Chronic inflammatory disorders and risk of type 2 diabetes mellitus, coronary heart disease, and stroke: a population-based cohort study. Circulation 130, 837–844 (2014). source
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PremisecitationIn a double-blind randomized controlled trial of more than 10,000 adults with prior myocardial infarction and elevated CRP, canakinumab given every 3 months lowered rates of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death compared with placebo, without changing LDL cholesterol.
“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”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [44] Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017). source
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PremisecitationIn 41 healthy volunteers of different ages, unstimulated IL-12p70 in women and CRP in men were associated with older age, while no effects were found for IL-1β, IFN-α, or TNF-α.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] Elisia, I. et al. Effect of age on chronic inflammation and responsiveness to bacterial and viral challenges. PLoS One 12, e0188881 (2017). source
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PremisecitationIn more than 160,000 people from North Glasgow, a combination of CRP above 10 mg/L, albumin above 35 mg/L, and neutrophil count predicted all-cause mortality over 8 years and mortality from cancer, cardiovascular disease, and cerebrovascular disease.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [45] Proctor, M. J. et al. Systemic inflammation predicts all-cause mortality: a Glasgow inflammation outcome study. PLoS One 10, e0116206 (2015). source
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PremisecitationA meta-analysis of eight randomized controlled trials with 260 participants found that anti-TNF-α inhibitor therapy significantly reduced insulin resistance and improved insulin sensitivity in patients with rheumatoid arthritis.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Burska, A. N., Sakthiswary, R. & Sattar, N. Effects of tumour necrosis factor antagonists on insulin sensitivity/resistance in rheumatoid arthritis: a systematic review and meta-analysis. PLoS One 10, e0128889 (2015). source
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InterpretationcitationGreater inflammatory activity is associated with older age, but not for all inflammatory markers, and these associations may partly reflect chronic ailments and frailty rather than biological aging itself.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] Elisia, I. et al. Effect of age on chronic inflammation and responsiveness to bacterial and viral challenges. PLoS One 12, e0188881 (2017). source
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PremisecitationCanonical biomarkers of acute inflammation predict morbidity and mortality in cross-sectional and longitudinal studies and may be used to index age-related systemic 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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [46] Arai, Y. et al. Inflammation, but not telomere length, predicts successful ageing at extreme old age: a longitudinal study of semi-supercentenarians. EBioMedicine 2, 1549–1558 (2015). source
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- Rests on an assumption: There are currently no standard biomarkers for indicating the presence of health-damaging chronic inflammation.
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PremisecitationRates of systemic chronic inflammation-related diseases have increased dramatically in older and younger individuals in industrialized countries with Western lifestyles but are relatively rare in non-Westernized populations whose diets, lifestyles, and ecological niches resemble those of most human evolution.
“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 evolution65–71.”
Quote in the paperSubstantial claim0 of 7 sources checked- cites [65] McDade, T. W. Early environments and the ecology of inflammation. Proc. Natl Acad. Sci. USA 109, 17281–17288 (2012). source
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- cites [66] Carrera-Bastos, P., Fontes-Villalba, M., O’Keefe, J. H., Lindeberg, S. & Cordain, L. The western diet and lifestyle and diseases of civilization. Res. Rep. Clin. Cardiol. 2, 15–35 (2011).
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- cites [67] Raichlen, D. A. et al. Physical activity patterns and biomarkers of cardiovascular disease risk in hunter-gatherers. Am. J. Hum. Biol. 29, e22919 (2017). source
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- cites [68] Kaplan, H. et al. Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study. Lancet 389, 1730–1739 (2017). source
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- cites [69] Lindeberg, S. & Lundh, B. Apparent absence of stroke and ischaemic heart disease in a traditional Melanesian island: a clinical study in Kitava. J. Intern. Med. 233, 269–275 (1993). source
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- cites [70] Lindeberg, S., Berntorp, E., Nilsson-Ehle, P., Terént, A. & Vessby, B. Age relations of cardiovascular risk factors in a traditional Melanesian society: the Kitava Study. Am. J. Clin. Nutr. 66, 845–852 (1997). source
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- cites [71] Lindeberg, S., Eliasson, M., Lindahl, B. & Ahrén, B. Low serum insulin in traditional Pacific Islanders—the Kitava Study. Metabolism 48, 1216–1219 (1999). source
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InterpretationcitationDifferences among older adults in the extent of systemic chronic inflammation are thought to reflect inter-individual differences in exposure to pro-inflammatory factors, although within-person studies are limited.
“The fact that differences exist in the extent to which older adults exhibit SCI52,64 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.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [52] Alpert, A. et al. A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring. Nat. Med. 25, 487–495 (2019). source
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- cites [64] Shen-Orr, S. S. & Furman, D. Variability in the immune system: of vaccine responses and immune states. Curr. Opin. Immunol. 25, 542–547 (2013). source
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PremisecitationNon-endogenous contributors to the senescence-associated secretory phenotype include chronic infections, lifestyle-induced obesity, microbiome dysbiosis, diet, social and cultural changes, and environmental and industrial toxicants.
“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.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [57] Effros, R. B. The silent war of CMV in aging and HIV infection. Mech. Ageing Dev. 158, 46–52 (2016). source
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- cites [58] Stout, M. B., Justice, J. N., Nicklas, B. J. & Kirkland, J. L. Physiological aging: links among adipose tissue dysfunction, diabetes, and frailty. Physiology (Bethesda) 32, 9–19 (2017).
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- cites [59] Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 159, 1–15 (2018).
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InterpretationreasoningHow senescent cells acquire the senescence-associated secretory phenotype is not fully understood, but existing research points to a combination of endogenous and non-endogenous social, environmental, and lifestyle risk factors.
“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.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationA multi-omics IMM-AGE metric in 135 adults described immune functioning better than chronological age and accurately predicted all-cause mortality.
“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”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [52] Alpert, A. et al. A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring. Nat. Med. 25, 487–495 (2019). source
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InterpretationcitationDietary and lifestyle habits and exposure to pollutants can increase oxidative stress, upregulate mitogenic signaling pathways, and cause genomic and epigenomic perturbations that induce the senescence-associated secretory phenotype.
“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 perturbations8,60,62,63 that can induce the SASP.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [8] Renz, H. et al. An exposome perspective: early-life events and immune development in a changing world. J. Allergy Clin. Immunol. 140, 24–40 (2017). source
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- cites [60] Zitvogel, L., Pietrocola, F. & Kroemer, G. Nutrition, inflammation and cancer. Nat. Immunol. 18, 843–850 (2017). source
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- cites [62] Carroll, J. E. et al. Partial sleep deprivation activates the DNA damage response (DDR) and the senescence-associated secretory phenotype (SASP) in aged adult humans. Brain Behav. Immun. 51, 223–229 (2016). source
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- cites [63] Yuan, J. et al. Long-term persistent organic pollutants exposure induced telomere dysfunction and senescence-associated secretary phenotype. J. Gerontol. A Biol. Sci. Med. Sci. 73, 1027–1035 (2018). source
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PremisecitationIn 210 healthy twins aged 8 to 82 years, non-heritable factors were the strongest contributors to differences in chronic inflammation across individuals, and environmental exposures called the exposome are the main drivers of systemic chronic inflammation.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [72] Brodin, P. et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37–47 (2015). source
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PremisecitationChronic HIV infection causes premature aging of the immune system and is associated with early cardiovascular and skeletal changes, attributed largely to accumulation of senescent CD8+ T cells that produce increased pro-inflammatory mediators.
“chronic infection with HIV causes premature aging of the immune system and is associated with early cardiovascular and skeletal changes57, with such effects being attributed in large part to the accumulation of senescent CD8+ T cells that produce increased levels of pro-inflammatory mediators80.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [57] Effros, R. B. The silent war of CMV in aging and HIV infection. Mech. Ageing Dev. 158, 46–52 (2016). source
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- cites [80] Chou, J. P., Ramirez, C. M., Wu, J. E. & Effros, R. B. Accelerated aging in HIV/AIDS: novel biomarkers of senescent human CD8+ T cells. PLoS One 8, e64702 (2013). source
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PremisecitationNon-industrialized populations that are minimally exposed to industrialized environments but highly exposed to microbes have very low rates of inflammation-related chronic disease and substantial fluctuations in inflammatory markers that do not increase with age.
“populations of hunter-gatherers and other existing non-industrialized societies such as the Shuar hunter-gatherers of the Ecuadorian Amazon83,84, Tsimané forager-horticulturalists of Bolivia68, Hadza hunter-gatherers from Tanzania67, subsistence agriculturalists from rural Ghana85 and traditional horticulturalists of Kitava (Papua New Guinea)86—all of whom are minimally exposed to industrialized”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [65] McDade, T. W. Early environments and the ecology of inflammation. Proc. Natl Acad. Sci. USA 109, 17281–17288 (2012). source
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- cites [67] Raichlen, D. A. et al. Physical activity patterns and biomarkers of cardiovascular disease risk in hunter-gatherers. Am. J. Hum. Biol. 29, e22919 (2017). source
Not checked in the free run.
- cites [68] Kaplan, H. et al. Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study. Lancet 389, 1730–1739 (2017). source
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- cites [83] McDade, T. W. et al. Analysis of variability of high sensitivity C-reactive protein in lowland Ecuador reveals no evidence of chronic low-grade inflammation. Am. J. Hum. Biol. 24, 675–681 (2012). source
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- cites [86] Agmon-Levin, N. et al. Antitreponemal antibodies leading to autoantibody production and protection from atherosclerosis in Kitavans from Papua New Guinea. Ann. N. Y. Acad. Sci. 1173, 675–682 (2009). source
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PremisecitationThese non-industrialized populations have higher physical activity, diets composed mainly of fresh or minimally processed foods, less exposure to environmental pollutants, circadian rhythms more synchronized with sunlight, and different social stressors from those in industrialized environments.
“Their lifestyles, for example, are characterized by higher levels of physical activity67,71,87, diets composed mainly of fresh or minimally processed food sources66,88,89, and less exposure to environmental pollutants66. In addition, individuals living in these environments generally have circadian rhythms that are more closely synchronized with diurnal fluctuations in sunlight exposure90 and the”
Quote in the paperSubstantial claim0 of 7 sources checked- cites [67] Raichlen, D. A. et al. Physical activity patterns and biomarkers of cardiovascular disease risk in hunter-gatherers. Am. J. Hum. Biol. 29, e22919 (2017). source
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- cites [71] Lindeberg, S., Eliasson, M., Lindahl, B. & Ahrén, B. Low serum insulin in traditional Pacific Islanders—the Kitava Study. Metabolism 48, 1216–1219 (1999). source
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- cites [87] Gurven, M., Jaeggi, A. V., Kaplan, H. & Cummings, D. Physical activity and modernization among Bolivian Amerindians. PLoS One 8, e55679 (2013). source
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- cites [66] Carrera-Bastos, P., Fontes-Villalba, M., O’Keefe, J. H., Lindeberg, S. & Cordain, L. The western diet and lifestyle and diseases of civilization. Res. Rep. Clin. Cardiol. 2, 15–35 (2011).
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- cites [88] Cordain, L. et al. Plant-animal subsistence ratios and macronutrient energy estimations in worldwide hunter-gatherer diets. Am. J. Clin. Nutr. 71, 682–692 (2000). source
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- cites [89] Kuipers, R. S., Joordens, J. C. A. & Muskiet, F. A. J. A multidisciplinary reconstruction of Palaeolithic nutrition that holds promise for the prevention and treatment of diseases of civilisation. Nutr. Res. Rev. 25, 96–129 (2012). source
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- cites [90] De la Iglesia, H. O. et al. Ancestral sleep. Curr. Biol. 26, R271–R272 (2016). source
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InterpretationreasoningChronic infections contribute to systemic chronic inflammation but are not likely to be its primary driver.
“while chronic infections appear to contribute to SCI, they are not likely the primary driver.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationWorldwide, 31% of individuals are physically inactive, with higher inactivity in high-income countries than in low-to-middle-income countries.
“One study showed that, worldwide, 31% of individuals are considered physically inactive—defined as not meeting the minimum international recommendations for regular physical activity—with levels of inactivity being higher in high-income countries than in low-to-middle-income countries93.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [93] Hallal, P. C. et al. Global physical activity levels: surveillance progress, pitfalls, and prospects. Lancet 380, 247–257 (2012). source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationApproximately 50% of American adults are considered physically inactive.
“In the United States, these numbers are even higher, with approximately 50% of American adults being considered physically inactive94.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [94] Katzmarzyk, P. T., Lee, I.-M., Martin, C. K. & Blair, S. N. Epidemiology of physical activity and exercise training in the United States. Prog. Cardiovasc. Dis. 60, 3–10 (2017). source
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InterpretationcitationThese effects can promote insulin resistance, dyslipidemia, endothelial dysfunction, high blood pressure, and sarcopenia, increasing risk for cardiovascular disease, type 2 diabetes, NAFLD, osteoporosis, various cancers, depression, dementia, and Alzheimer's disease in chronically inactive individuals.
“These effects can, in turn, promote several inflammation-related pathophysiologic alterations, including insulin resistance, dyslipidemia, endothelial dysfunction, high blood pressure and loss of muscle mass (sarcopenia)100, that have been found to increase risk for a variety of conditions, including CVD, type 2 diabetes, NAFLD, osteoporosis, various types of cancer, depression, dementia and”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [95] Fiuza-Luces, C. et al. Exercise benefits in cardiovascular disease: beyond attenuation of traditional risk factors. Nat. Rev. Cardiol. 15, 731–743 (2018). source
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- cites [100] Booth, F. W., Roberts, C. K. & Laye, M. J. Lack of exercise is a major cause of chronic diseases. Compr. Physiol. 2, 1143–1211 (2012). source
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May combine two claims.
PremisecitationIndustrialization decreased infant mortality and increased average life expectancy through social stability, reduced physical trauma, modern medical technology, and public health measures such as sanitation, quarantine, and vaccination.
“Industrialization conferred many benefits, including social stability; reduced 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 expectancy66.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [66] Carrera-Bastos, P., Fontes-Villalba, M., O’Keefe, J. H., Lindeberg, S. & Cordain, L. The western diet and lifestyle and diseases of civilization. Res. Rep. Clin. Cardiol. 2, 15–35 (2011).
Not checked in the free run.
May combine two claims.
PremisecitationSkeletal muscle is an endocrine organ that releases myokines during contraction, which can systemically reduce inflammation.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [95] Fiuza-Luces, C. et al. Exercise benefits in cardiovascular disease: beyond attenuation of traditional risk factors. Nat. Rev. Cardiol. 15, 731–743 (2018). source
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PremisecitationVisceral adipose tissue is an active endocrine, immunological, and metabolic organ that expands mainly through adipocyte hypertrophy, leading to hypoxia and cell death, activation of hypoxia-inducible factor-1α, increased reactive oxygen species, and release of damage-associated molecular patterns.
“VAT is an active endocrine, immunological and metabolic organ composed of various cells (including immune cells, such as resident macrophages) that expands mostly through adipocyte hypertrophy, which can lead to areas of hypoxia and even cell death, resulting in activation of hypoxia-inducible factor-1α, increased production of reactive oxygen species, and release of DAMPs”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [105] Schipper, H. S., Prakken, B., Kalkhoven, E. & Boes, M. Adipose tissue-resident immune cells: key players in immunometabolism. Trends Endocrinol. Metabol. 23, 407–415 (2012). source
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- cites [106] Tchernof, A. & Després, J.-P. Pathophysiology of human visceral obesity: an update. Physiol. Rev. 93, 359–404 (2013). source
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- cites [107] Pellegrinelli, V., Carobbio, S. & Vidal-Puig, A. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues. Diabetologia 59, 1075–1088 (2016). source
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- cites [108] Frasca, D., Blomberg, B. B. & Paganelli, R. Aging, obesity, and inflammatory age-related diseases. Front. Immunol. 8, 1745 (2017). source
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PremisecitationA meta-analysis of 1,683,693 participants found that moving from physically inactive to 150 minutes per week of moderate-intensity aerobic activity was associated with lower cardiovascular disease mortality by 23%, cardiovascular disease incidence by 17%, and type 2 diabetes incidence by 26% over an average follow-up of 12.8 years.
“A recent meta-analysis of studies with cohorts from Europe, the United States and the rest of the world that included 1,683,693 participants found that going from physically inactive to achieving the recommended 150 minutes of moderate-intensity aerobic activity per week was associated with lower risk of CVD mortality by 23%, CVD incidence by 17%, and type 2 diabetes incidence by 26% during an”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [101] Wahid, A. et al. Quantifying the association between physical activity and cardiovascular disease and diabetes: a systematic review and meta-analysis. J. Am. Heart Assoc. 5, e002495 (2016). source
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InterpretationcitationPhysical inactivity increases risk for non-communicable diseases because it is linked to obesity and excessive visceral adipose tissue, which is a significant trigger of inflammation.
“physical inactivity can increase individuals’ risk for various non-communicable diseases because it is linked to obesity100 and, in particular, excessive visceral adipose tissue (VAT), which is a significant trigger of inflammation104–106.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [100] Booth, F. W., Roberts, C. K. & Laye, M. J. Lack of exercise is a major cause of chronic diseases. Compr. Physiol. 2, 1143–1211 (2012). source
Not checked in the free run.
- cites [104] Pérez, L. M. et al. ‘Adipaging’: ageing and obesity share biological hallmarks related to a dysfunctional adipose tissue. J. Physiol. 594, 3187–3207 (2016). source
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- cites [105] Schipper, H. S., Prakken, B., Kalkhoven, E. & Boes, M. Adipose tissue-resident immune cells: key players in immunometabolism. Trends Endocrinol. Metabol. 23, 407–415 (2012). source
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- cites [106] Tchernof, A. & Després, J.-P. Pathophysiology of human visceral obesity: an update. Physiol. Rev. 93, 359–404 (2013). source
Not checked in the free run.
May combine two claims. The quote only partly states this claim.
PremisecitationData from 1.44 million participants across prospective cohort studies showed that physically inactive individuals had more than 20% greater risk of several cancers, including esophageal adenocarcinoma, liver, lung, kidney, gastric cardia, and endometrial cancers and myeloid leukemia, after adjusting for adiposity and smoking except for lung cancer.
“data from 1.44 million participants across several prospective cohort studies revealed that, as compared to individuals exhibiting high levels of leisure-time physical activity (≥90th percentile), those who were physically inactive (≤10th percentile) had a greater risk (>20%) of developing several cancers, including esophageal adenocarcinoma; liver, lung, kidney, gastric cardia and endometrial”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [102] Moore, S. C. et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern. Med. 176, 816–825 (2016). source
Not checked in the free run.
May combine two claims.
InterpretationcitationTNF-α and other molecules cause adipocyte insulin resistance, increasing lipolysis and lipid spillover to the pancreas and liver, where they contribute to beta-cell dysfunction, hepatic insulin resistance, and fatty liver.
“TNF-α and other molecules can cause adipocyte insulin resistance, which increases lipolysis, with the resulting spillover of lipids into other organs, such as the pancreas and liver, where they can contribute to beta-cell dysfunction, hepatic insulin resistance and fatty liver106.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [106] Tchernof, A. & Després, J.-P. Pathophysiology of human visceral obesity: an update. Physiol. Rev. 93, 359–404 (2013). source
Not checked in the free run.
May combine two claims.
InterpretationcitationThese obesity-inflammation dynamics occur in adults and first emerge during childhood.
“These dynamics are known to occur in adults and can promote age-related disease risk, but they first emerge during childhood26.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Singer, K. & Lumeng, C. N. The initiation of metabolic inflammation in childhood obesity. J. Clin. Invest. 127, 65–73 (2017). source
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May combine two claims.
InterpretationcitationVisceral obesity accelerates aging and increases risk for cardiometabolic, neurodegenerative, and autoimmune diseases and several types of cancer.
“visceral obesity accelerates aging and increases risk for cardiometabolic, neurodegenerative and autoimmune diseases, as well as several types of cancer19,104,106,110–112.”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [19] Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018). source
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- cites [104] Pérez, L. M. et al. ‘Adipaging’: ageing and obesity share biological hallmarks related to a dysfunctional adipose tissue. J. Physiol. 594, 3187–3207 (2016). source
Not checked in the free run.
- cites [106] Tchernof, A. & Després, J.-P. Pathophysiology of human visceral obesity: an update. Physiol. Rev. 93, 359–404 (2013). source
Not checked in the free run.
- cites [110] Versini, M., Jeandel, P.-Y., Rosenthal, E. & Shoenfeld, Y. Obesity in autoimmune diseases: not a passive bystander. Autoimm. Rev. 13, 981–1000 (2014). source
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- cites [111] Himbert, C. et al. Signals from the adipose microenvironment and the obesity-cancer link–a systematic review. Cancer Prev. Res. (Phila.) 10, 494–506 (2017). source
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- cites [112] van Dijk, G. et al. Integrative neurobiology of metabolic diseases, neuroinflammation, and neurodegeneration. Front. Neurosci. 9, 173 (2015). source
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May combine two claims. The quote only partly states this claim.
InterpretationcitationThese events induce secretion of pro-inflammatory molecules by adipocytes, endothelial cells, and adipose immune cells, leading to infiltration of immune cells and a reduction in T regulatory cells, amplifying inflammation that can become prolonged and systemic.
“These events can induce the secretion of numerous pro-inflammatory molecules, including adipokines, cytokines (for example, IL-1β, IL-6, TNF-α), and chemokines (especially monocyte chemoattractant protein-1) by adipocytes, endothelial cells and resident adipose tissue immune cells (for example, macrophages)105–108. This in turn leads to the infiltration of various immune cells in the VAT,”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [106] Tchernof, A. & Després, J.-P. Pathophysiology of human visceral obesity: an update. Physiol. Rev. 93, 359–404 (2013). source
Not checked in the free run.
- cites [107] Pellegrinelli, V., Carobbio, S. & Vidal-Puig, A. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues. Diabetologia 59, 1075–1088 (2016). source
Not checked in the free run.
- cites [108] Frasca, D., Blomberg, B. B. & Paganelli, R. Aging, obesity, and inflammatory age-related diseases. Front. Immunol. 8, 1745 (2017). source
Not checked in the free run.
- cites [109] Grant, R. W. & Dixit, V. D. Adipose tissue as an immunological organ. Obesity (Silver Spring) 23, 512–518 (2015). source
Not checked in the free run.
May combine two claims.
InterpretationcitationEndotoxemia is a suspected cause of inflammation through activation of pattern recognition receptors such as Toll-like receptors in immune cells and of inflammation-mediated metabolic conditions such as insulin resistance.
“the latter is a suspected cause of inflammation through activation of pattern recognition receptors, such as Toll-like receptors, in immune cells and of inflammation-mediated metabolic conditions such as insulin resistance118.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [118] Jayashree, B. et al. Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes. Mol. Cell. Biochem. 388, 203–210 (2014). source
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PremisecitationThe typical diet widely adopted in many countries over the past 40 years is relatively low in fruits, vegetables, and other fiber- and prebiotic-rich foods and high in refined grains, alcohol, ultra-processed foods, and emulsifiers.
“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.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [66] Carrera-Bastos, P., Fontes-Villalba, M., O’Keefe, J. H., Lindeberg, S. & Cordain, L. The western diet and lifestyle and diseases of civilization. Res. Rep. Clin. Cardiol. 2, 15–35 (2011).
Not checked in the free run.
- cites [123] Sonnenburg, E. D. & Sonnenburg, J. L. The ancestral and industrialized gut microbiota and implications for human health. Nat. Rev. Microbiol. 17, 383–390 (2019). source
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- cites [124] Bentley, J. U.S. trends in food availability and a dietary assessment of loss-adjusted food availability, 1970-2014. EIB-166, U.S. Department of Agriculture, Economic Research Service (2017).
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- cites [125] Martínez Steele, E. et al. Ultra-processed foods and added sugars in the US diet: evidence from a nationally representative cross-sectional study. BMJ Open 6, e009892 (2016). source
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Probably not a substantial claim: may not pass S1 (asserted).
InterpretationcitationA complex balance in the intestinal ecosystem, if disrupted, can compromise its function and integrity and cause low-grade systemic chronic inflammation.
“it has been hypothesized that a complex balance exists in the intestinal ecosystem that, if disrupted, can compromise its function and integrity and in turn cause low-grade SCI59.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [59] Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 159, 1–15 (2018).
Not checked in the free run.
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PremisecitationSerum zonulin concentrations appear elevated in obese children and adults and in persons with type 2 diabetes, NAFLD, coronary heart disease, polycystic ovary syndrome, autoimmune diseases, and cancer.
“serum concentrations of zonulin, a protein that increases intestinal permeability, appear to be elevated in obese children and adults117,119, and in persons with type 2 diabetes118, NAFLD, coronary heart disease, polycystic ovary syndrome, autoimmune diseases and cancer117.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [117] Sturgeon, C. & Fasano, A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers 4, e1251384 (2016). source
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- cites [119] Küme, T. et al. The relationship between serum zonulin level and clinical and laboratory parameters of childhood obesity. J. Clin. Res. Pediatr. Endocrinol. 9, 31–38 (2017). source
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- cites [118] Jayashree, B. et al. Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes. Mol. Cell. Biochem. 388, 203–210 (2014). source
Not checked in the free run.
May combine two claims.
PremisecitationObesity, which is strongly linked to changes in the gut microbiome, is associated with increased intestinal paracellular permeability and endotoxemia.
“Obesity, which is strongly linked to changes in the gut microbiome, has also been associated with increased intestinal paracellular permeability and endotoxemia114,117.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [114] Cani, P. D. & Jordan, B. F. Gut microbiota-mediated inflammation in obesity: a link with gastrointestinal cancer. Nat. Rev. Gastroenterol. Hepatol. 15, 671–682 (2018). source
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- cites [117] Sturgeon, C. & Fasano, A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers 4, e1251384 (2016). source
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PremisecitationHigh salt intake shifts macrophages toward a pro-inflammatory state, marked by more naive CD4+ T cells becoming TH-17 cells and less expression and anti-inflammatory action of T regulatory cells.
“salt has been shown to skew macrophages toward a pro-inflammatory phenotype characterized by the increased differentiation of naive CD4+ T cells into T helper (TH)-17 cells, which are highly inflammatory, and decreased expression and anti-inflammatory activity of T regulatory cells135”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [135] Muller, D. N., Wilck, N., Haase, S., Kleinewietfeld, M. & Linker, R. A. Sodium in the microenvironment regulates immune responses and tissue homeostasis. Nat. Rev. Immunol. 19, 243–254 (2019). source
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InterpretationcitationThese dietary factors can alter gut microbiota composition and function and are linked to increased intestinal permeability and epigenetic changes in the immune system that ultimately cause low-grade endotoxemia and systemic chronic inflammation.
“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.”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [123] Sonnenburg, E. D. & Sonnenburg, J. L. The ancestral and industrialized gut microbiota and implications for human health. Nat. Rev. Microbiol. 17, 383–390 (2019). source
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- cites [127] Chassaing, B., Van de Wiele, T., De Bodt, J., Marzorati, M. & Gewirtz, A. T. Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation. Gut 66, 1414–1427 (2017). source
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- cites [128] Zmora, N., Bashiardes, S., Levy, M. & Elinav, E. The role of the immune system in metabolic health and disease. Cell Metab. 25, 506–521 (2017). source
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- cites [129] Richards, J. L., Yap, Y. A., McLeod, K. H., Mackay, C. R. & Mariño, E. Dietary metabolites and the gut microbiota: an alternative approach to control inflammatory and autoimmune diseases. Clin. Trans. Immunol. 5, e82 (2016). source
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- cites [130] Bishehsari, F. et al. Alcohol and gut-derived inflammation. Alcohol Res. 38, 163–171 (2017).
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- cites [131] Lerner, A. & Matthias, T. Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease. Autoimm. Rev. 14, 479–489 (2015). source
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PremisecitationOrally absorbed advanced glycation and lipoxidation end-products formed during food processing or when foods are cooked at high temperatures and low humidity are appetite increasing and linked to overnutrition, obesity, and inflammation.
“orally absorbed advanced glycation and lipoxidation end-products that are formed during the processing of foods or when foods are cooked at high temperatures and in low-humidity conditions are appetite increasing and are linked to overnutrition and hence obesity and inflammation132.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [132] Vlassara, H. & Striker, G. E. AGE restriction in diabetes mellitus: a paradigm shift. Nat. Rev. Endocrinol. 7, 526–539 (2011). source
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PremisecitationWhen combined with low physical activity, eating hyperpalatable processed foods high in fat, sugar, salt and flavor additives can trigger major shifts in cell metabolism, leading to greater production and faulty disposal of dysfunctional organelles such as mitochondria, and to misplaced, misfolded and oxidized endogenous molecules.
“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”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [30] Franceschi, C., Garagnani, P., Vitale, G., Capri, M. & Salvioli, S. Inflammaging and ‘garb-aging’. Trends Endocrinol. Metab. 28, 199–212 (2017). source
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- cites [60] Zitvogel, L., Pietrocola, F. & Kroemer, G. Nutrition, inflammation and cancer. Nat. Immunol. 18, 843–850 (2017). source
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- cites [148] van Niekerk, G., Toit, du, A., Loos, B. & Engelbrecht, A.-M. Nutrient excess and autophagic deficiency: explaining metabolic diseases in obesity. Metab. Clin. Exp. 82, 14–21 (2018). source
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationA systematic analysis of dietary data from 195 countries identified poor diet as the leading risk factor for death in 2017, with excessive sodium intake accounting for more than half of diet-related deaths.
“a recent systematic analysis of dietary data from 195 different countries identified poor diet as the main risk factor for death in 2017, with excessive sodium intake being responsible for more than half of diet-related deaths146”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [146] GBD 2017 Diet Collaborators. Health effects of dietary risks in 195 countries, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 393, 1958–1972 (2019). source
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PremisecitationLong-chain omega-3 fatty acids are precursors to resolvins, maresins and protectins, which participate in resolving inflammation.
“they are precursors to molecules such as resolvins, maresins and protectins that are involved in the resolution of inflammation28,29”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [28] Serhan, C. N. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92–101 (2014). source
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- cites [29] Serhan, C. N. & Levy, B. D. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J. Clin. Invest. 128, 2657–2669 (2018). source
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PremisecitationThe Lactobacillus population is important for health because it controls TH17 cells and strengthens the intestinal epithelial barrier, thereby lowering systemic inflammation.
“This specific population is critical for health as it regulates TH17 cells and enhances the integrity of the intestinal epithelial barrier, thus reducing systemic inflammation135”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [135] Muller, D. N., Wilck, N., Haase, S., Kleinewietfeld, M. & Linker, R. A. Sodium in the microenvironment regulates immune responses and tissue homeostasis. Nat. Rev. Immunol. 19, 243–254 (2019). source
Not checked in the free run.
May combine two claims.
PremisecitationThe main drivers of the rising global prevalence of low omega-3 status are low fish intake and high intake of vegetable oils rich in linoleic acid, which pushes omega-3 fatty acids out of cell membrane phospholipids.
“The main contributors to the growing worldwide incidence of low omega-3 status are a low intake of fish and high intake of vegetable oils that are high in linoleic acid, which displaces omega-3 fatty acids in cell membrane phospholipids140,141”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [140] Blasbalg, T. L., Hibbeln, J. R., Ramsden, C. E., Majchrzak, S. F. & Rawlings, R. R. Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. Am. J. Clin. Nutr. 93, 950–962 (2011). source
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- cites [141] Calder, P. C. Very long-chain n-3 fatty acids and human health: fact, fiction and the future. Proc. Nutr. Soc. 77, 52–72 (2018). source
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PremisecitationDeficiencies in zinc and magnesium, caused by eating processed or refined foods low in vitamins and minerals, can promote inflammation and may contribute to SCI.
“These factors include deficiencies in micronutrients, including zinc137 and magnesium138, which are caused by eating processed or refined foods that are low in vitamins and minerals”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [137] Bonaventura, P., Benedetti, G., Albarède, F. & Miossec, P. Zinc and its role in immunity and inflammation. Autoimm. Rev. 14, 277–285 (2015). source
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- cites [138] Nielsen, F. H. Effects of magnesium depletion on inflammation in chronic disease. Curr. Opin. Clin. Nutr. Metab. Care 17, 525–530 (2014). source
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PremisecitationRandomized controlled trials have shown that omega-3 fatty acid supplementation lowers inflammation and may have health-promoting effects.
“various RCTs have shown that omega-3 fatty acid supplementation reduces inflammation142–144 and may thus have health-promoting effects141–144”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [142] Kiecolt-Glaser, J. K. et al. Omega-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial. Brain Behav. Immun. 25, 1725–1734 (2011). source
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- cites [143] Kiecolt-Glaser, J. K. et al. Omega-3 supplementation lowers inflammation in healthy middle-aged and older adults: a randomized controlled trial. Brain Behav. Immun. 26, 988–995 (2012). source
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- cites [144] AbuMweis, S., Jew, S., Tayyem, R. & Agraib, L. Eicosapentaenoic acid and docosahexaenoic acid containing supplements modulate risk factors for cardiovascular disease: a meta-analysis of randomised placebo-control human clinical trials. J. Hum. Nutr. Diet. 31, 67–84 (2017). source
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PremisecitationChanges in social interactions and sleep quality brought by the industrial revolution and modern era can promote SCI and insulin resistance, which in turn raise risk for obesity, type 2 diabetes, cardiovascular disease and all-cause mortality.
“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”
Quote in the paperNot a substantial claim0 of 8 sources checked- cites [59] Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 159, 1–15 (2018).
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- cites [91] Slavich, G. M. & Cole, S. W. The emerging field of human social genomics. Clin. Psychol. Sci. 1, 331–348 (2013). source
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- cites [149] Slavich, G. M. & Irwin, M. R. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol. Bull. 140, 774–815 (2014). source
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- cites [150] Tobaldini, E. et al. Short sleep duration and cardiometabolic risk: from pathophysiology to clinical evidence. Nat. Rev. Cardiol. 16, 213–224 (2019). source
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- cites [151] Reutrakul, S. & Van Cauter, E. Sleep influences on obesity, insulin resistance, and risk of type 2 diabetes. Metab. Clin. Exp. 84, 56–66 (2018). source
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- cites [152] Valtorta, N. K., Kanaan, M., Gilbody, S., Ronzi, S. & Hanratty, B. Loneliness and social isolation as risk factors for coronary heart disease and stroke: systematic review and meta-analysis of longitudinal observational studies. Heart 102, 1009–1016 (2016). source
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- cites [153] Steptoe, A., Shankar, A., Demakakos, P. & Wardle, J. Social isolation, loneliness, and all-cause mortality in older men and women. Proc. Natl Acad. Sci. USA 110, 5797–5801 (2013). source
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- cites [154] Kivimaki, M. & Steptoe, A. Effects of stress on the development and progression of cardiovascular disease. Nat. Rev. Cardiol. 15, 215–229 (2018). source
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May combine two claims.
PremisecitationThese altered molecules increase with age and can act as DAMPs that innate immune cells detect, activating the inflammasome machinery, amplifying inflammation, and contributing to inflammaging.
“These altered molecules, which increase with age19,30, can be recognized as DAMPs by innate immune cells, which in turn activate the inflammasome machinery, amplify the inflammatory response1,30,60 and contribute to a biological state that has been called “inflammaging,””
Quote in the paperSubstantial claim0 of 3 sources checked- cites [1] Furman, D. et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat. Med. 23, 174–184 (2017). source
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- cites [30] Franceschi, C., Garagnani, P., Vitale, G., Capri, M. & Salvioli, S. Inflammaging and ‘garb-aging’. Trends Endocrinol. Metab. 28, 199–212 (2017). source
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- cites [60] Zitvogel, L., Pietrocola, F. & Kroemer, G. Nutrition, inflammation and cancer. Nat. Immunol. 18, 843–850 (2017). source
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May combine two claims.
PremisecitationIncreased exposure to artificial light, especially blue light, at atypical biological times increases arousal and alertness at night and causes circadian rhythm disruption.
“increased exposure to artificial light, especially the blue spectrum, at atypical biologic times157–159. Exposure to blue light, especially after sundown, increases arousal and alertness at night and thus causes circadian rhythm disruption158,159”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [157] Lunn, R. M. et al. Health consequences of electric lighting practices in the modern world: a report on the National Toxicology Program’s workshop on shift work at night, artificial light at night, and circadian disruption. Sci. Total Environ. 607–608, 1073–1084 (2017). source
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- cites [158] Hatori, M. et al. Global rise of potential health hazards caused by blue light-induced circadian disruption in modern aging societies. NPJ Aging Mech. Dis. 3, 9 (2017). source
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- cites [159] Touitou, Y., Reinberg, A. & Touitou, D. Association between light at night, melatonin secretion, sleep deprivation, and the internal clock: health impacts and mechanisms of circadian disruption. Life Sci. 173, 94–106 (2017). source
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May combine two claims.
PremisecitationPsychological stressors that persist in some contemporary work environments, such as high job demand and low control, can cause physiological changes that impair glucocorticoids' ability to down-regulate inflammatory activity because chronic cortisol elevation reduces sensitivity, leading to SCI and poor health.
“psychological stressors that are persistently present in some contemporary work environments, such as those characterized by high job demand and low control, can cause physiologic changes155 that disrupt the ability for glucocorticoids to effectively down-regulate inflammatory activity due to decreased sensitivity caused by chronic elevation in cortisol, leading in turn to SCI and poor health156”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [155] Chandola, T., Brunner, E. & Marmot, M. Chronic stress at work and the metabolic syndrome: prospective study. BMJ 332, 521–525 (2006). source
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- cites [156] Cohen, S. et al. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc. Natl Acad. Sci. USA 109, 5995–5999 (2012). source
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May combine two claims.
PremisecitationCircadian rhythm disruption promotes inflammation and is a risk factor for multiple inflammation-related diseases.
“which in turn promotes inflammation160, and is a risk for multiple inflammation-related diseases157,159”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [160] Leproult, R., Holmbäck, U. & Van Cauter, E. Circadian misalignment augments markers of insulin resistance and inflammation, independently of sleep loss. Diabetes 63, 1860–1869 (2014). source
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- cites [157] Lunn, R. M. et al. Health consequences of electric lighting practices in the modern world: a report on the National Toxicology Program’s workshop on shift work at night, artificial light at night, and circadian disruption. Sci. Total Environ. 607–608, 1073–1084 (2017). source
Not checked in the free run.
- cites [159] Touitou, Y., Reinberg, A. & Touitou, D. Association between light at night, melatonin secretion, sleep deprivation, and the internal clock: health impacts and mechanisms of circadian disruption. Life Sci. 173, 94–106 (2017). source
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May combine two claims.
PremisecitationThese compounds promote inflammatory activity through multiple mechanisms, including cytotoxicity, oxidative stress, and endocrine disruption beginning in utero.
“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”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [8] Renz, H. et al. An exposome perspective: early-life events and immune development in a changing world. J. Allergy Clin. Immunol. 140, 24–40 (2017). source
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- cites [162] Sly, P. D. et al. Health consequences of environmental exposures: causal thinking in global environmental epidemiology. Ann. Glob. Health 82, 3–9 (2016). source
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May combine two claims.
PremisecitationThese chemicals are thought to contribute causally to hormone-dependent cancers, metabolic syndrome, type 2 diabetes, hypertension, cardiovascular disease, allergy and asthma, and autoimmune and neurodegenerative diseases.
“These chemicals are thus suspected of playing a causal role in hormone-dependent cancers, metabolic syndrome, type 2 diabetes, hypertension, CVD, allergy and asthma, and autoimmune and neurodegenerative diseases8,162,166”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [8] Renz, H. et al. An exposome perspective: early-life events and immune development in a changing world. J. Allergy Clin. Immunol. 140, 24–40 (2017). source
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- cites [162] Sly, P. D. et al. Health consequences of environmental exposures: causal thinking in global environmental epidemiology. Ann. Glob. Health 82, 3–9 (2016). source
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- cites [166] Floreani, A., Leung, P. S. C. & Gershwin, M. E. Environmental basis of autoimmunity. Clin. Rev. Allergy Immunol. 50, 287–300 (2016). source
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May combine two claims.
PremisecitationNight-shift work raises risk for metabolic syndrome and is thought to contribute causally to obesity, type 2 diabetes, cardiovascular disease, and breast, ovarian, prostate, colorectal and pancreatic cancer.
“night-shift work has been found to increase risk for the metabolic syndrome and is suspected of being a causal factor in obesity, type 2 diabetes and CVD, as well as in breast, ovarian, prostate, colorectal and pancreatic cancer157”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [157] Lunn, R. M. et al. Health consequences of electric lighting practices in the modern world: a report on the National Toxicology Program’s workshop on shift work at night, artificial light at night, and circadian disruption. Sci. Total Environ. 607–608, 1073–1084 (2017). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe estimated share of human disease burden attributed to environmental chemicals has grown, prompting a shift toward high-throughput screening and translational systems-toxicology approaches.
“The concomitant increase in the estimated contribution of environmental chemicals to human disease burden162 has prompted a shift toward data generation using high-throughput screening to investigate the effect of industrial toxicants on cellular pathways, which has been supported by initiatives like the US Federal Tox21 Program, and toward the adoption of translational systems-toxicology”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [162] Sly, P. D. et al. Health consequences of environmental exposures: causal thinking in global environmental epidemiology. Ann. Glob. Health 82, 3–9 (2016). source
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- cites [163] Collins, F. S., Gray, G. M. & Bucher, J. R. Toxicology. Transforming environmental health protection. Science 319, 906–907 (2008). source
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Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenEach year, an estimated 2,000 new chemicals are introduced into items individuals use or ingest daily, such as foods, personal care items, prescription drugs, household cleaners and lawn care products.
“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”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe Tox21 Program has tested more than 9,000 chemicals using more than 1,600 assays and demonstrated that numerous commonly encountered chemicals greatly alter molecular signaling pathways underlying inflammation and inflammation-related disease risk.
“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”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [164] Kleinstreuer, N. C. et al. Phenotypic screening of the ToxCast chemical library to classify toxic and therapeutic mechanisms. Nat. Biotechnol. 32, 583–591 (2014). source
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May combine two claims.
PremisecitationThe immune system is programmed during the prenatal period and is affected by epigenetic changes induced by maternal environmental exposures-such as infectious agents, diet, psychological stress and xenobiotics-both in the womb and before conception, with paternal factors possibly also exerting epigenetic effects.
“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 effect26,128,171”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [26] Singer, K. & Lumeng, C. N. The initiation of metabolic inflammation in childhood obesity. J. Clin. Invest. 127, 65–73 (2017). source
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- cites [128] Zmora, N., Bashiardes, S., Levy, M. & Elinav, E. The role of the immune system in metabolic health and disease. Cell Metab. 25, 506–521 (2017). source
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- cites [171] Macpherson, A. J., de Agüero, M. G. & Ganal-Vonarburg, S. C. How nutrition and the maternal microbiota shape the neonatal immune system. Nat. Rev. Immunol. 17, 508–517 (2017). source
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May combine two claims.
PremisecitationEarly-life psychological stress-from abuse, neglect, maltreatment, bullying or low socioeconomic conditions-can intensify neural threat responses, increase inflammatory activity, change immune competence, and produce SCI across the lifespan.
“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 lifecycle27,169”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [170] Slavich, G. M., Way, B. M., Eisenberger, N. I. & Taylor, S. E. Neural sensitivity to social rejection is associated with inflammatory responses to social stress. Proc. Natl Acad. Sci. USA 107, 14817–14822 (2010). source
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- cites [27] Olvera Alvarez, H. A., Kubzansky, L. D., Campen, M. J. & Slavich, G. M. Early life stress, air pollution, inflammation, and disease: an integrative review and immunologic model of social-environmental adversity and lifespan health. Neurosci. Biobehav. Rev. 92, 226–242 (2018). source
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- cites [169] Fagundes, C. P., Glaser, R. & Kiecolt-Glaser, J. K. Stressful early life experiences and immune dysregulation across the lifespan. Brain Behav. Immun. 27, 8–12 (2013). source
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PremisecitationObese children often become obese adolescents and adults, so a pro-inflammatory phenotype often continues into adulthood for those who were obese as children.
“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”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Singer, K. & Lumeng, C. N. The initiation of metabolic inflammation in childhood obesity. J. Clin. Invest. 127, 65–73 (2017). source
Not checked in the free run.
The paper relies on this without support.
There are currently no standard biomarkers for indicating the presence of health-damaging chronic inflammation.
“there are presently no standard biomarkers for indicating the presence of health-damaging chronic inflammation.”
The authors state this as an assumption.
An evolutionary mismatch between human physiology and industrialized lifestyles is a major cause of systemic chronic inflammation.
“This is believed to have created an evolutionary mismatch in humans—characterized by an increasing separation from their ecological niche—and this mismatch, in turn, has been hypothesized to be a major cause of SCI65,66,82,89,92.”
The authors state this as an assumption.
Maternal inflammation during pregnancy passes an inflammatory code through epigenetic modifications to offspring, leading to elevated SCI risk in childhood and adulthood and intergenerational transmission of risk.
“In this model (Fig. 2), SCI and disease risk are hypothesized to be perpetuated transgenerationally.”
“maternal inflammation during pregnancy172,173 is believed to pass an inflammatory ‘code’ through epigenetic modifications to the offspring”
The paper relies on this without support.
A majority of older adults experience down-regulation of immune response components, leading to increased susceptibility to viral infections and weakened vaccine responses.
“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.”
The paper relies on this without support.
No study to date has assessed the entire human exposome over the entire developmental trajectory.
“no study to date has assessed the entire human exposome over the entire developmental trajectory”
The paper relies on this without support.
Only a few studies have investigated how modifying SCI-related processes may benefit human health or longevity.
“only a few studies have investigated how modifying SCI-related processes may benefit human health or longevity”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Reductions in CRP levels can be achieved by lifestyle interventions that promote better overall health.
“Reductions in CRP levels can be instead achieved by lifestyle interventions that promote better overall health (Furman et al., 2019).”
From Treatment of periodontitis and <scp>C</scp> ‐reactive protein: A systematic review and meta‐analysis of randomized clinical trials (2023) · cites this paper as Furman et al., 2019
The Physical activity section says muscle contraction can reduce systemic inflammation and links low activity to higher CRP levels. That supports physical activity as a route to lower CRP, but it does not directly report CRP reductions from a lifestyle intervention; the Future directions section says studies showing reduced chronic inflammation after targeting lifestyle factors remain limited. (LLM, conf=0.81)
Experimental — accuracy not yet measuredSystemic inflammation as assessed by high CRP levels raises the future risk of chronic diseases and their complications like diabetes, renal and CVDs.
“Systemic inflammation as assessed by high CRP levels raises the future risk of chronic diseases and their complications like diabetes, renal and CVDs (Libby et al., 2018; Furman et al., 2019).”
From Treatment of periodontitis and <scp>C</scp> ‐reactive protein: A systematic review and meta‐analysis of randomized clinical trials (2023) · cites this paper as Furman et al., 2019
The section “Systemic chronic inflammation and non-communicable disease risk” links systemic chronic inflammation to type 2 diabetes, chronic kidney disease and CVD, and reports that elevated CRP predicts cardiovascular events. It does not establish that high CRP predicts future diabetes or kidney disease; it also describes the CRP–CVD finding as an association rather than proof that CRP raises risk. (LLM, conf=0.86)
Experimental — accuracy not yet measuredInflammation promotes oxidation through inflammatory mediators.
“At the same time, inflammation promotes oxidation through inflammatory mediators.205,206”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [206]
The ‘Systemic chronic inflammation and non-communicable disease risk’ section says systemic chronic inflammation can damage tissues by inducing oxidative stress. That supports the inflammation-to-oxidation link, but the passage does not say that inflammatory mediators are the mechanism. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPeriodontitis is a source of low-grade chronic systemic inflammation via haematogenous dissemination of periodontal bacteria or spillover of inflammatory mediators, contributing to systemic inflammatory burden and increasing risk of chronic diseases like CVD.
“Periodontitis is a local inflammation and a source of low-grade chronic inflammation, which results from haematogenous dissemination of periodontal bacteria or spillover of inflammatory mediators from periodontal tissues to the bloodstream [4, 9], thus contributing to the systemic inflammatory burden, increasing the risk of several chronic diseases like CVD, type II diabetes mellitus (T2DM), renal”
From Effect of non-surgical periodontal therapy on risk markers of cardiovascular disease: a systematic review and meta-analysis (2024) · cites this paper as [10]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredChronic inflammation greatly increases the risk for LOAD.
“Chronic inflammation has been shown to greatly increase the risk for LOAD (Furman et al., 2019).”
From Plcg2M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer’s Disease-Relevant Phenotypes in Mice (2022) · cites this paper as Furman et al., 2019
The section “Systemic chronic inflammation and non-communicable disease risk” lists neurodegenerative diseases among the risks associated with systemic chronic inflammation. It also reports lower Alzheimer’s disease risk among rheumatoid arthritis patients treated with etanercept. Neither passage establishes that chronic inflammation greatly increases the risk of late-onset Alzheimer’s disease (LOAD) specifically; page numbers are not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Systemic inflammation is implicated in the onset and progression of several chronic diseases.
“Low‐grade inflammation has been however linked to several chronic diseases like cardiovascular diseases (CVDs), type II diabetes mellitus (T2DM), renal diseases (CKD), cancer and neurodegenerative disorders (Furman et al., 2019).”
From Treatment of periodontitis and <scp>C</scp> ‐reactive protein: A systematic review and meta‐analysis of randomized clinical trials (2023) · cites this paper as Furman et al., 2019
The immune system undergoes numerous and profound changes with aging.
“The immune system undergoes numerous and profound changes with aging, which are extensively reviewed elsewhere (3–5).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [5]
Efforts to characterize inflammation in humans have relied on one or a few inflammatory proteins, with IL-6, TNF-α, and CRP being the most widely used.
“Efforts to characterize inflammation in humans have relied on one or a few inflammatory proteins, with IL-6, TNF-α, and CRP being the most widely used (5).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [5]
Inflammageing is generally accepted to result from accumulated exogenous and endogenous stresses over time and to be mediated mainly by immune cells and senescent cells.
“It is generally accepted that inflammageing occurs in response to an accumulation of exogeneous and endogenous physiological stresses over time and is primarily mediated by immune cells and senescent cells (Figure 1)14,15.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [15]
Inflammageing is recognized as a hallmark of ageing and a key driver of disease, including ageing-associated diseases, and is a prominent risk factor for morbidity and death.
“Inflammageing is now being recognized as a hallmark of ageing and a key driver of disease (FIG. 3Aa), including ageing-associated diseases, and has been described as a prominent risk factor for morbidity and death95–97.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [97]
Endogenous cytoDNA contributes to sterile inflammation, which is linked to chronic age-associated conditions such as cancer, cardiovascular disease, and neurodegenerative disorders.
“Endogenous cytoDNA is a contributor to so-called sterile inflammation, inflammation in the absence of pathogenic infection, which is associated with many chronic age-associated conditions, including cancer, cardiovascular disease, and neurodegenerative disorders (Ferrucci and Fabbri, 2018; Franceschi et al., 2007; Furman et al., 2019).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Furman et al., 2019
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- Authors
- Furman, D., Campisi, J., Verdin, E., Carrera-Bastos, P., Targ, S., Franceschi, C., Ferrucci, L., Gilroy, D. W., Fasano, A., Miller, G. W., Miller, A. H., Mantovani, A., Weyand, C. M., Barzilai, N., Goronzy, J. J., Rando, T. A., Effros, R. B., Lucia, A., Kleinstreuer, N., & Slavich, G. M.
- Affiliations
- Buck Institute for Research on Aging (US)
- University of California, San Francisco (US)
- N. I. Lobachevsky State University of Nizhny Novgorod (RU)
- National Institute on Aging (US)
- University College London (GB)
- Harvard University (US)
- Columbia University Irving Medical Center (US)
- Emory University (US)
- Humanitas University (IT)
- Stanford Medicine (US)
- Albert Einstein College of Medicine (US)
- VA Palo Alto Health Care System (US)
- University of California, Los Angeles (US)
- National Institutes of Health (US)
- Corresponding author
- Furman, David
- ORCID
- Venue
- Nature Medicine
- Published
- 2019-12
- Volume
- 25
- Issue
- 12
- Pages
- 1822-1832
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC7147972
- OpenAlex
- W2993908729
- Cited by
- 4,915
- References
- 181
- Citations by year
- 2026: 783 · 2025: 953 · 2024: 969 · 2023: 839 · 2022: 691 · 2021: 465 · 2020: 210 · 2019: 2 · 2017: 1
- FWCI
- 49.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ABACUS. Repositorio de Producción Científica (Universidad Europea) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health
- Stanford Center on Longevity
- Buck Institute for Research on Aging
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- chronic systemic inflammation, lifespan, cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, autoimmune disease, neurodegenerative diseases, infection, physical inactivity, unhealthy diet, environmental toxins, industrial toxicants, psychological stress, early diagnosis, prevention, treatment
- MeSH terms
- Autoimmune Diseases, Cardiovascular Diseases, Chronic Disease, Diabetes Mellitus, Humans, Inflammation, Life Style, Longevity, Neoplasms, Risk Factors, Neurodegenerative Diseases, Renal Insufficiency, Chronic, Non-alcoholic Fatty Liver Disease
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