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Cited by 3,690Frailty in Older AdultsAtherosclerosis and Cardiovascular DiseasesInflammasome and immune disorders

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

Open access
Ferrucci, Luigi, Fabbri, Elisa·2018·Nature Reviews Cardiology
DOI 10.1038/s41569-018-0064-2PMC PMC6146930
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Abstract

Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty - which affect clinical manifestations, prognosis, and response to treatment - and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials.

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Crossref · 10.1038/s41569-018-0064-2

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  • Premisecitation

    Inflammageing is a risk factor for cardiovascular disease.

    “Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal.”
    • Also stated in: § Abstract · boosted
      “Strong evidence indicates that inflammageing is a risk factor for cardiovascular disease (CVD), in addition to many age-associated chronic diseases and other adverse health outcomes.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [9] Ruparelia, N., Chai, J. T., Fisher, E. A. & Choudhury, R. P. Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat. Rev. Cardiol. 14, 133–144 (2017). source

      Not checked in the free run.

    • cites [10] Leonardi, G. C., Accardi, G., Monastero, R., Nicoletti, F. & Libra, M. Ageing: from inflammation to cancer. Immun. Ageing 15, 1 (2018). source

      Not checked in the free run.

    • cites [11] Salimi, S. et al. Inflammation and trajectory of renal function in community-dwelling older adults. J. Am. Geriatr. Soc. 66, 804–811 (2018). source

      Not checked in the free run.

    • cites [12] Gorelick, P. B. Role of inflammation in cognitive impairment: results of observational epidemiological studies and clinical trials. Ann. NY Acad. Sci. 1207, 155–162 (2010). source

      Not checked in the free run.

    • cites [13] 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

      Not checked in the free run.

    • cites [14] Fabbri, E. et al. Aging and the burden of multimorbidity: associations with inflammatory and anabolic hormonal biomarkers. J. Gerontol. A. Biol. Sci. Med. Sci. 70, 63–70 (2015). source

      Not checked in the free run.

    • cites [15] Ferrucci, L. et al. Serum IL-6 level and the development of disability in older persons. J. Am. Geriatr. Soc. 47, 639–646 (1999). source

      Not checked in the free run.

    • cites [16] Kuo, H., Bean, J. F., Yen, C. & Leveille, S. G. Linking C-reactive protein to late-life disability in the National Health and Nutrition Examination Survey (NHANES) 1999-2002. J. Gerontol. A. Biol. Sci. Med. Sci. 61, 380–387 (2006). source

      Not checked in the free run.

    • cites [17] Schaap, L. A. et al. Higher inflammatory marker levels in older persons: associations with 5-year change in muscle mass and muscle strength. J. Gerontol. A. Biol. Sci. Med. Sci. 64, 1183–1189 (2009). source

      Not checked in the free run.

    • cites [18] Soysal, P. et al. Inflammation and frailty in the elderly: a systematic review and meta-analysis. Ageing Res. Rev. 31, 1–8 (2016). source

      Not checked in the free run.

    • Rests on an assumption: Blood levels of inflammatory markers adequately reflect inflammageing and its biological effects.
  • Interpretationreasoning

    Multimorbidity and frailty in older patients with cardiovascular disease are associated with inflammation through mechanisms similar to those in cardiovascular disease.

    “This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty — which affect clinical manifestations, prognosis, and response to treatment — and are associated with inflammation by mechanisms similar to those in CVD.”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    Clinical trials suggest that the link between inflammageing and cardiovascular disease is causal.

    “Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    High levels of age-associated pro-inflammatory markers are detected in most older individuals even without risk factors and clinically active diseases.

    “High levels of age-associated pro-inflammatory markers are detected in the majority of older individuals, even in the absence of risk factors and clinically active diseases3,5–7.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [3] Ferrucci, L. et al. Proinflammatory state, hepcidin, and anemia in older persons. Blood 115, 3810–3816 (2010). source

      Not checked in the free run.

    • cites [5] Cohen, H. J., Pieper, C. F., Harris, T., Rao, K. M. & Currie, M. S. The association of plasma IL-6 levels with functional disability in community-dwelling elderly. J. Gerontol. A. Biol. Sci. Med. Sci. 52, M201–M208 (1997). source

      Not checked in the free run.

    • cites [6] Newman, A. B. et al. Trajectories of function and biomarkers with age: the CHS All Stars Study. Int. J. Epidemiol. 45, 1135–1145 (2016). source

      Not checked in the free run.

    • cites [7] Gerli, R. et al. Chemokines, sTNF-Rs and sCD30 serum levels in healthy aged people and centenarians. Mech. Ageing Dev. 121, 37–46 (2000). source

      Not checked in the free run.

  • Premisecitation

    According to the antagonistic pleiotropy theory of ageing, inflammation might have been evolutionarily selected for early-life benefits but becomes detrimental in old age.

    “According to the antagonistic pleiotropy theory of ageing, inflammation might have been evolutionarily selected because of beneficial effects early in life and in adulthood, although it becomes detrimental in old age when the effect of natural selection is no longer active8.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] 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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  • May combine two claims. 70
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Premisenone given

    Most older people develop inflammageing, a state marked by raised blood inflammatory markers, and this state is linked to high vulnerability to chronic illness, disability, frailty, and early death.

    “Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Blood levels of inflammatory markers adequately reflect inflammageing and its biological effects.

  • May combine two claims.

    Premisecitation

    Inflammageing is a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia.

    “Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [9] Ruparelia, N., Chai, J. T., Fisher, E. A. & Choudhury, R. P. Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat. Rev. Cardiol. 14, 133–144 (2017). source

      Not checked in the free run.

    • cites [10] Leonardi, G. C., Accardi, G., Monastero, R., Nicoletti, F. & Libra, M. Ageing: from inflammation to cancer. Immun. Ageing 15, 1 (2018). source

      Not checked in the free run.

    • cites [11] Salimi, S. et al. Inflammation and trajectory of renal function in community-dwelling older adults. J. Am. Geriatr. Soc. 66, 804–811 (2018). source

      Not checked in the free run.

    • cites [12] Gorelick, P. B. Role of inflammation in cognitive impairment: results of observational epidemiological studies and clinical trials. Ann. NY Acad. Sci. 1207, 155–162 (2010). source

      Not checked in the free run.

    • cites [13] 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

      Not checked in the free run.

    • cites [14] Fabbri, E. et al. Aging and the burden of multimorbidity: associations with inflammatory and anabolic hormonal biomarkers. J. Gerontol. A. Biol. Sci. Med. Sci. 70, 63–70 (2015). source

      Not checked in the free run.

    • cites [15] Ferrucci, L. et al. Serum IL-6 level and the development of disability in older persons. J. Am. Geriatr. Soc. 47, 639–646 (1999). source

      Not checked in the free run.

    • cites [16] Kuo, H., Bean, J. F., Yen, C. & Leveille, S. G. Linking C-reactive protein to late-life disability in the National Health and Nutrition Examination Survey (NHANES) 1999-2002. J. Gerontol. A. Biol. Sci. Med. Sci. 61, 380–387 (2006). source

      Not checked in the free run.

    • cites [17] Schaap, L. A. et al. Higher inflammatory marker levels in older persons: associations with 5-year change in muscle mass and muscle strength. J. Gerontol. A. Biol. Sci. Med. Sci. 64, 1183–1189 (2009). source

      Not checked in the free run.

    • cites [18] Soysal, P. et al. Inflammation and frailty in the elderly: a systematic review and meta-analysis. Ageing Res. Rev. 31, 1–8 (2016). source

      Not checked in the free run.

    • Rests on an assumption: Blood levels of inflammatory markers adequately reflect inflammageing and its biological effects.

  • May combine two claims.

    Premisenone given

    Older patients with cardiovascular disease often have multimorbidity and frailty, which affect clinical manifestations, prognosis, and treatment response.

    “This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty — which affect clinical manifestations, prognosis, and response to treatment — and are associated with inflammation by mechanisms similar to those in CVD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Epidemiological studies have found inflammageing is a risk factor for CVD, cancer, chronic kidney disease, dementia, depression, multimorbidity, mobility disability, ADL disability, sarcopenia, frailty, and premature death.

    “Epidemiological studies have found that inflammageing is a risk factor for CVD, cancer, chronic kidney disease, dementia, and depression as well for global indicators of poor health status, such as multimorbidity, mobility disability and disability in activities of daily living, sarcopenia, frailty, and premature death9–19.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [9] Ruparelia, N., Chai, J. T., Fisher, E. A. & Choudhury, R. P. Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat. Rev. Cardiol. 14, 133–144 (2017). source

      Not checked in the free run.

    • cites [10] Leonardi, G. C., Accardi, G., Monastero, R., Nicoletti, F. & Libra, M. Ageing: from inflammation to cancer. Immun. Ageing 15, 1 (2018). source

      Not checked in the free run.

    • cites [11] Salimi, S. et al. Inflammation and trajectory of renal function in community-dwelling older adults. J. Am. Geriatr. Soc. 66, 804–811 (2018). source

      Not checked in the free run.

    • cites [12] Gorelick, P. B. Role of inflammation in cognitive impairment: results of observational epidemiological studies and clinical trials. Ann. NY Acad. Sci. 1207, 155–162 (2010). source

      Not checked in the free run.

    • cites [13] 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

      Not checked in the free run.

    • cites [14] Fabbri, E. et al. Aging and the burden of multimorbidity: associations with inflammatory and anabolic hormonal biomarkers. J. Gerontol. A. Biol. Sci. Med. Sci. 70, 63–70 (2015). source

      Not checked in the free run.

    • cites [15] Ferrucci, L. et al. Serum IL-6 level and the development of disability in older persons. J. Am. Geriatr. Soc. 47, 639–646 (1999). source

      Not checked in the free run.

    • cites [16] Kuo, H., Bean, J. F., Yen, C. & Leveille, S. G. Linking C-reactive protein to late-life disability in the National Health and Nutrition Examination Survey (NHANES) 1999-2002. J. Gerontol. A. Biol. Sci. Med. Sci. 61, 380–387 (2006). source

      Not checked in the free run.

    • cites [17] Schaap, L. A. et al. Higher inflammatory marker levels in older persons: associations with 5-year change in muscle mass and muscle strength. J. Gerontol. A. Biol. Sci. Med. Sci. 64, 1183–1189 (2009). source

      Not checked in the free run.

    • cites [18] Soysal, P. et al. Inflammation and frailty in the elderly: a systematic review and meta-analysis. Ageing Res. Rev. 31, 1–8 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Many researchers propose inflammageing is a marker of accelerated ageing and one of the pillars of the biology of ageing.

    “On the basis of these findings, many researchers have proposed that inflammageing is a marker of accelerated ageing and should be considered to be one of the pillars of the biology of ageing20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Hodes, R. J. et al. Disease drivers of aging. Ann. NY Acad. Sci. 1386, 45–68 (2016). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The hypothesis that inflammation affects cardiovascular disease, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans.

    “The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Ageing is associated with immune dysregulation, most evident as high blood levels of pro-inflammatory immunogenic stimulations.

    “Ageing is associated with immune dysregulation, of which the most evident characteristics are high blood levels of pro-inflammatory immunogenic stimulations3,4.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Ferrucci, L. et al. Proinflammatory state, hepcidin, and anemia in older persons. Blood 115, 3810–3816 (2010). source

      Not checked in the free run.

    • cites [4] Fulop, T. et al. Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? Frontiers Immunol. 8, 1960 (2018). source

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    Premisecitation

    The IL1RN rs4251961 minor allele is associated with lower serum IL-1RN, and rs579543 is independently associated with IL-1RN levels.

    “Examining common variants of the IL1RN gene revealed that the rs4251961 minor allele is associated with a lowered serum level of IL-1RN and that the rs579543 single nucleotide polymorphism (SNP) is also independently associated with IL-1RN levels, whereas the IL1RN 1018 haplotype correlates with higher concentrations of IL-1β and IFNγ22.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Rafiq, S. et al. Common genetic variation in the gene encoding interleukin-1-receptor antagonist (IL-1RA) is associated with altered circulating IL-1RA levels. Genes Immun. 8, 344–351 (2007). source

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    Premisecitation

    IL1RN variants affect the pathophysiology of human infections and the risk of insulin resistance and knee osteoarthritis.

    “These findings have been confirmed in three independent cohorts26, and further research has demonstrated that these factors affect the pathophysiology of human infections27 and the risk of developing insulin resistance28 and knee osteoarthritis29.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [27] Carrol, E. D. et al. The IL1RN promoter rs4251961 correlates with IL-1 receptor antagonist concentrations in human infection and is differentially regulated by GATA-1. J. Immunol. 186, 2329–2335 (2011). source

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    • cites [28] Herder, C. et al. Genetic determinants of circulating interleukin-1 receptor antagonist levels and their association with glycemic traits. Diabetes 63, 4343–4359 (2014). source

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    • cites [29] Wu, X. et al. IL-1 receptor antagonist gene as a predictive biomarker of progression of knee osteoarthritis in a population cohort. Osteoarthr. Cartil. 21, 930–938 (2013). source

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    Premisenone given

    The IL6 -174G>C SNP magnifies IL-6 production in response to inflammatory stimuli but is inconsistently associated with baseline IL-6 levels.

    “A SNP in the promoter region of IL6 at position−174G > C magnifies IL-6 production in response to inflammatory stimuli, but this SNP has been associated inconsistently with baseline IL-6 levels.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Carriers of the IL6 -174G>C mutation have increased risk of Alzheimer disease, CVD, non-insulin-dependent diabetes mellitus, bone fragility, and systemic-onset juvenile chronic arthritis.

    “Carriers of the−174G > C mutation have an increased risk of developing various major diseases, including Alzheimer disease30, CVD31, non-insulin-dependent diabetes mellitus32, bone fragility33, and systemic-onset juvenile chronic arthritis34.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [30] Dai, L., Liu, D., Guo, H., Wang, Y. & Bai, Y. Association between polymorphism in the promoter region of interleukin 6 (-174 G/C) and risk of Alzheimer’s disease: a meta-analysis. Neurol. J. 259, 414–419 (2012). source

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    • cites [31] Hou, H. et al. Association of interleukin-6 gene polymorphism with coronary artery disease: an updated systematic review and cumulative meta-analysis. Inflamm. Res. 64, 707–720 (2015). source

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    • cites [32] Testa, R. et al. Interleukin-6-174 G > C polymorphism affects the association between IL-6 plasma levels and insulin resistance in type 2 diabetic patients. Diabetes Res. Clin. Pract. 71, 299–305 (2006). source

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    Premisecitation

    Multiple SNPs in CRP are associated with higher CRP levels and increased risk of myocardial infarction and CVD-related death.

    “Multiple SNPs in the CRP gene are associated with higher CRP levels and increased risk of myocardial infarction and CVD-related death38.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Lange, L. A. et al. Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JAMA 296, 2703 (2006). source

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    Premisecitation

    Variants in IL6R are associated with increased risk of coronary artery disease, rheumatoid arthritis, atrial fibrillation, abdominal aortic aneurysm, asthma, type 1 diabetes, and depression.

    “Variants in the IL6R gene have been found to be associated with increased risk of coronary artery disease24, rheumatoid arthritis, atrial fibrillation, and abdominal aortic aneurysm, and with increased susceptibility to asthma, type 1 diabetes, and depression36,37.”
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    • cites [24] Swerdlow, D. I. et al. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet 379, 1214–1224 (2012). source

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    • cites [36] Khandaker, G. M., Zammit, S., Burgess, S., Lewis, G. & Jones, P. B. Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort. Brain. Behav. Immun. 69, 264–272 (2017). source

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    • cites [37] Ferreira, R. C. et al. Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases. PLoS Genet. 9, e1003444 (2013). source

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    Premisecitation

    A few gene transcripts mediate the age-IL-6 association, with SLC4A10 mRNA explaining as much as 19% of this association.

    “A few gene transcripts mediate the age–IL-6 association, among which the largest affected transcript, SLC4A10 mRNA (encoding the sodium-driven chloride bicarbonate exchanger), explains as much as 19% of this association40.”
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    • cites [40] Pilling, L. C. et al. Gene expression markers of age-related inflammation in two human cohorts. Exp. Gerontol. 70, 37–45 (2015). source

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    Premisereasoning

    Findings on age-related miRNA differences are inconsistent, possibly due to differences in sample size, age composition, health status, and detection methods.

    “Findings from these studies are inconsistent, possibly owing to differences in sample size, age composition, and health status of the examined individuals, and because miRNA detection methods vary widely in specificity, accuracy, and sensitivity.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Adipocytes in abdominal, intramuscular, liver, and pericardial fat can produce pro-inflammatory and chemotactic compounds such as IL-6, IL-1β, TNF, and CCL2, as well as hormones that modulate inflammation such as adiponectin and leptin.

    “Adipocytes in abdominal, intramuscular, liver, and pericardial fat can produce pro-inflammatory and chemotactic compounds, such as IL-6, IL-1β, TNF, and C-C motif chemokine 2 (CCL2), as well as hormones that modulate inflammation, such as adiponectin and leptin54.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–189 (2011). source

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    Premisecitation

    miR-25-3p, miR-92a-3p, miR-93-5p, miR-101-3p, miR-106b-5p, miR-142-5p, miR-151a-3p, and miR-181a-5p tend to be under-represented, whereas miR-21-5p and miR-126-3p are over-represented at older ages.

    “Nonetheless, miR-25–3p, miR-92a-3p, miR-93–5p, miR-101–3p, miR-106b-5p, miR-142–5p, miR-151a-3p, and miR-181a-5p tend to be under-represented, whereas miR-21–5p and miR-126–3p are over-represented at older ages47,49,50.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [47] Ameling, S. et al. Associations of circulating plasma microRNAs with age, body mass index and sex in a population-based study. BMC Med. Genomics 8, 61 (2015). source

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    • cites [50] Olivieri, F. et al. Age- and glycemia-related miR-126-3p levels in plasma and endothelial cells. Aging (Albany. NY). 6, 771–787 (2014). source

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    Premisecitation

    Weight loss combined with exercise improves functional status and reduces some features of frailty in obese older individuals, improves cardiovascular risk profile, and reduces risk of CVD.

    “Weight loss combined with exercise improves functional status and reduces some of the features of frailty in obese older individuals, improves the cardiovascular risk profile, and reduces the risk of CVD, although whether these beneficial effects are caused by reduced inflammation remains unclear63–65.”
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    • cites [63] Zomer, E. et al. Interventions that cause weight loss and the impact on cardiovascular risk factors: a systematic review and meta-analysis. Obes. Rev. 17, 1001–1011 (2016). source

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    • cites [64] Ma, C. et al. Effects of weight loss interventions for adults who are obese on mortality, cardiovascular disease, and cancer: systematic review and meta-analysis. BMJ 359, j4849 (2017). source

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    • cites [65] Villareal, D. T. et al. Aerobic or resistance exercise, or both, in dieting obese older adults. N. Engl. J. Med. 376, 1943–1955 (2017). source

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    Premisecitation

    Activated monocytes that give rise to M1 and M2 macrophages produce more inflammatory compounds that probably appear in the circulation.

    “Activated monocytes that give rise to M1 and M2 macrophages produce even more inflammatory compounds that probably appear in the circulation57.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003). source

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    Premisecitation

    The number of B lymphocytes and macrophages in visceral adipose tissue from obese individuals is increased and correlated with BMI.

    “The number of B lymphocytes and macrophages in visceral adipose tissue from obese individuals is also increased and is correlated with BMI55.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Frasca, D. & Blomberg, B. B. Adipose tissue inflammation induces B cell inflammation and decreases B cell function in aging. Front. Immunol. 8, 1003 (2017). source

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    Premisecitation

    As beneficial intestinal bacteria decrease with ageing, other bacteria increase in relative abundance, including pathobionts.

    “As beneficial intestinal bacteria decrease in abundance with ageing, other bacteria increase in relative abundance, including symbiotic bacteria that can become pathogenic under inflamed conditions, often termed pathobionts69.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Rampelli, S. et al. Functional metagenomic profiling of intestinal microbiome in extreme ageing. Aging 5, 902–912 (2013). source

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    Premisecitation

    Increased gut dysbiosis has been postulated to increase mucosal barrier permeability, allowing bacteria and their products into the circulatory system and contributing to a chronic pro-inflammatory state.

    “Increased gut dysbiosis has been postulated to increase mucosal barrier permeability, thereby allowing bacteria and their products — including pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and microbial-associated molecular patterns (MAMPs)— into the circulatory system. Together, these factors contribute to a chronic pro-inflammatory state71.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Zapata, H. J. & Quagliarello, V. J. The microbiota and microbiome in aging: potential implications in health and age-related diseases. Am. J. Geriatr. Soc 63, 776–781 (2015). source

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    Premisecitation

    The theory that gut dysbiosis increases permeability and leakage of pro-inflammatory products is supported by animal models, but no definitive evidence exists in older individuals free from overt inflammatory disease.

    “This theory is supported by studies in animal models, but no definitive evidence exists of increased gut permeability and leakage of pro-inflammatory products in older individuals who are free from overt inflammatory disease72.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Thevaranjan, N. et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe 21, 455–466.e4 (2017). source

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    Premisecitation

    Beneficial commensal microorganisms normally counteract expansion of pathogenic microbial communities and maintain intestinal barrier integrity by fermenting starches and dietary fibres and producing mucus and lipid metabolites such as short-chain fatty acids.

    “The disappearance of these microorganisms is important because they normally counteract the expansion of pathogenic microbial communities, while also maintaining intestinal barrier integrity by fermenting starches and dietary fibres and producing mucus and lipid metabolites, such as short-chain fatty acids (primarily acetate, propionate, and butyrate)66–68.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [66] Mariat, D. et al. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol. 9, 123 (2009). source

      Not checked in the free run.

    • cites [67] Biagi, E. et al. Gut microbiota and extreme longevity. Curr. Biol. 26, 1480–1485 (2016). source

      Not checked in the free run.

    • cites [68] Shapiro, H., Thaiss, C. A., Levy, M. & Elinav, E. The cross talk between microbiota and the immune system: metabolites take center stage. Curr. Opin. Immunol. 30, 54–62 (2014). source

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  • May combine two claims.

    Premisecitation

    Changes in gut microbiota composition are associated with increased frailty, possibly due to gut dysbiosis-induced inflammation.

    “Of note, changes in gut microbiota composition have been shown to be associated with increased frailty74–76, which could be owing to gut dysbiosis-induced inflammation.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [74] van Tongeren, S. P., Slaets, J. P. J., Harmsen, H. J. M. & Welling, G. W. Fecal microbiota composition and frailty. Appl. Environ. Microbiol. 71, 6438–6442 (2005). source

      Not checked in the free run.

    • cites [75] O’Toole, P. W. & Jeffery, I. B. Gut microbiota and aging. Science 350, 1214–1215 (2015). source

      Not checked in the free run.

    • cites [76] Mello, A. M., Paroni, G., Daragjati, J. & Pilotto, A. Gastrointestinal microbiota and their contribution to healthy aging. Dig. Dis. 34, 194–201 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ageing is associated with a reduction in beneficial commensal microorganisms such as Coprococcus, Faecalibacterium, and Lactobacillus, and a decrease in the Firmicutes:Bacteroidetes ratio.

    “Despite large variability in the gut microbiota found in different populations, geographic regions, and settings, evidence suggests that ageing is associated with a reduction in beneficial commensal microorganisms — such as Coprococcus, Faecalibacterium, and Lactobacillus — as well as a decrease in the Firmicutes: Bacteroidetes ratio66–68.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [66] Mariat, D. et al. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol. 9, 123 (2009). source

      Not checked in the free run.

    • cites [67] Biagi, E. et al. Gut microbiota and extreme longevity. Curr. Biol. 26, 1480–1485 (2016). source

      Not checked in the free run.

    • cites [68] Shapiro, H., Thaiss, C. A., Levy, M. & Elinav, E. The cross talk between microbiota and the immune system: metabolites take center stage. Curr. Opin. Immunol. 30, 54–62 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pathobionts are enriched in the gut of older adults and are primarily dominated by facultative anaerobes such as Fusobacterium and Staphylococcus, a state associated with increased plasma inflammatory cytokines.

    “This category of microorganisms is enriched in the gut of older adults and is primarily dominated by facultative anaerobes — such as Fusobacterium and Staphylococcus — a state that has been associated with increased levels of inflammatory cytokines in plasma8,70.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Franceschi, C., Garagnani, P., Vitale, G., Capri, M. & Salvioli, S. Inflammaging and ‘garb-aging’. Trends Endocrinol. Metab 28, 199–212 (2017). source

      Not checked in the free run.

    • cites [70] Biagi, E. et al. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS ONE 5, e10667 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent cells are recognized by markers including p16INK4A and increased lysosome β-galactosidase activity, although these markers are neither fully sensitive nor specific and no gold-standard biomarker of cellular senescence has been established.

    “Senescent cells are recognized by specific markers, including cyclin-dependent kinase inhibitor 2A (commonly known as p16INK4A) and increased lysosome β-galactosidase activity, although these markers are neither fully sensitive nor specific and, despite intense research, no gold-standard biomarker of cellular senescence has been established90.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Bernardes de Jesus, B. & Blasco, M. A. Assessing cell and organ senescence biomarkers. Circ. Res. 111, 97–109 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Calorie restriction causes changes in microbiota composition, decreases inflammation, and improves gut barrier integrity.

    “Consistent with the notion that changes in the gut microbiota composition can affect healthy ageing, calorie restriction — the most powerful strategy to increase longevity in animal models — causes changes in microbiota composition, decreases inflammation, and improves gut barrier integrity80.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Ott, B. et al. Effect of caloric restriction on gut permeability, inflammation markers, and fecal microbiota in obese women. Sci. Rep. 7, 11955 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Centenarians have enrichment of Akkermansia, Bifidobacterium, and Christensenellaceae in their intestinal flora, which promote positive immune function, have anti-inflammatory activity, diminish effects of obesity, and contribute to metabolic homeostasis.

    “Centenarians, who can be considered extreme examples of healthy ageing, have an enrichment of Akkermansia, Bifidobacterium, and Christensenellaceae in their intestinal flora67, which promote positive immune function, have anti-inflammatory activity, diminish the effects of obesity, and contribute to metabolic homeostasis77–79.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [67] Biagi, E. et al. Gut microbiota and extreme longevity. Curr. Biol. 26, 1480–1485 (2016). source

      Not checked in the free run.

    • cites [77] Barrios, C. et al. Gut-microbiota-metabolite axis in early renal function decline. PLoS ONE 10, e0134311 (2015). source

      Not checked in the free run.

    • cites [78] Everard, A. et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl Acad. Sci. USA 110, 9066–9071 (2013). source

      Not checked in the free run.

    • cites [79] Turroni, F. et al. Molecular dialogue between the human gut microbiota and the host: a Lactobacillus and Bifidobacterium perspective. Cell. Mol. Life Sci. 71, 183–203 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some studies have shown that probiotics, prebiotics, or a combination can reduce systemic inflammation and progression of central obesity, but more research is needed.

    “Some studies have shown that this strategy can reduce systemic inflammation and progression of central obesity, but more research in this area is needed to substantiate this initial evidence and to assess whether the reduction of inflammation owing to microbiota changes has beneficial effects on health84,85.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [84] Nagpal, R. et al. Gut microbiota in health and disease: an overview focused on metabolic inflammation. Benef. Microbes 7, 181–194 (2016). source

      Not checked in the free run.

    • cites [85] Turchet, P., Laurenzano, M., Auboiron, S. & Antoine, J. M. Effect of fermented milk containing the probiotic Lactobacillus casei DN-114001 on winter infections in free-living elderly subjects: a randomised, controlled pilot study. J. Nutr. Health Aging 7, 75–77 (2003).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SNPs located near regulators of senescence and inflammation are particularly associated with diseases of ageing such as cancer, CVD, and type 2 diabetes, with the strongest association at a variant in CDKN2A encoding p16INK4A.

    “Interestingly, SNPs located near regulators of senescence and inflammation are particularly associated with diseases of ageing, such as cancer, CVD, and type 2 diabetes, and the strongest association was found with a variant in the CDKN2A gene, which encodes the p16INK4A protein that is over-expressed in many forms of senescence.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [91] Jeck, W. R., Siebold, A. P. & Sharpless, N. E. Review: a meta-analysis of GWAS and age-associated diseases. Aging Cell 11, 727–731 (2012). source

      Not checked in the free run.

    • cites [92] Johnson, S. C., Dong, X., Vijg, J. & Suh, Y. Genetic evidence for common pathways in human age-related diseases. Aging Cell 14, 809–817 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SASP molecules mainly function in a paracrine fashion and can facilitate senescence in neighbouring cells, but some soluble mediators are released into the circulation and likely contribute to inflammageing.

    “These secretory molecules mainly function in a paracrine fashion and can facilitate the development of cellular senescence in neighbouring cells, but some of the soluble mediators are released into the circulation and are likely to contribute to inflammageing96.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Borodkina, A. V., Deryabin, P. I., Giukova, A. A. & Nikolsky, N. N. ‘Social life’ of senescent sells: what is SASP and why study it? Acta Naturae 10, 4–14 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Senescence seems to be associated with ageing, inflammation, CVD, and impaired physical function in older individuals, making cell senescence a strong candidate mechanism for inflammageing.

    “Therefore, senescence seems to be associated with ageing, inflammation, CVD, and impaired physical function in older individuals, making cell senescence a strong candidate as a mechanism for inflammageing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Senescent T cell accumulation has been demonstrated in patients with chronic infections such as CMV or HIV, which might explain why these patients have chronically elevated pro-inflammatory markers and reduced vaccine efficacy.

    “Of note, senescent T cell accumulation has been demonstrated in patients with chronic infections such as Cytomegalovirus (CMV) or human immunodeficiency virus (HIV) infection, which might explain why patients with CMV or HIV infection have chronically elevated levels of pro-inflammatory markers and reduced vaccine efficacy108–110.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [108] Klenerman, P. & Oxenius, A. T cell responses to cytomegalovirus. Nat. Rev. Immunol. 16, 367–377 (2016). source

      Not checked in the free run.

    • cites [109] Sansoni, P. et al. New advances in CMV and immunosenescence. Exp. Gerontol. 55, 54–62 (2014). source

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    • cites [110] Fulop, T., Larbi, A. & Pawelec, G. Human T cell aging and the impact of persistent viral infections. Front. Immunol. 4, 271 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, clearance of p16INK4A-positive cells extends lifespan and slows emergence of ageing phenotypes and age-related functional deterioration of organs and tissues.

    “In mice, the clearance of p16INK4A-positive cells extends lifespan and slows the emergence of ageing phenotypes and age-related functional deterioration of organs and tissues111,112.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [111] Baker, D. J. et al. Clearance of p16 Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). source

      Not checked in the free run.

    • cites [112] Baker, D. J. et al. Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Strong evidence from mouse studies indicates that blockade of the NLRP3 inflammasome extends healthspan, attenuating multiple age-related degenerative changes linked to inflammageing, including insulin resistance, thymic involution, T cell senescence, bone loss, and physical and cognitive function decline.

    “In humans, IL-18 blood levels increase with ageing, and strong evidence from mouse studies indicates that blockade of the NLRP3 inflammasome extends healthspan, attenuating multiple age-related degenerative changes that have been linked to inflammageing, including insulin resistance, thymic involution, T cell senescence, and bone loss as well as physical and cognitive function decline114,117,118.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [114] Youm, Y. H. et al. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. 18, 519–532 (2013). source

      Not checked in the free run.

    • cites [117] Kepp, O., Galluzzi, L. & Kroemer, G. Mitochondrial control of the NLRP3 inflammasome. Nat. Immunol. 12, 199–200 (2011). source

      Not checked in the free run.

    • cites [118] Ferrucci, L. et al. The origins of age-related proinflammatory state. Blood 105, 2294–2299 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Accumulation of DAMPs is sensed by the NLRP3 inflammasome and causes NLRP3 oligomerization, resulting in caspase 1-dependent secretion of IL-1β and IL-18.

    “For example, accumulation of DAMPs is sensed by the NLRP3 inflammasome and causes NLRP3 oligomerization, resulting in caspase 1-dependent secretion of the inflammatory cytokines IL-1β and IL-18.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    In the era of HAART, patients with HIV infection have a life expectancy on average only slightly lower than the general population.

    “In the era of highly active antiretroviral therapy (HAART), patients with HIV infection have a life expectancy that is, on average, only slightly lower than in the general population.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Some studies have found that human CMV infection in older individuals is associated with increased cardiovascular and all-cause mortality, negative immune risk profile, inflammageing, and lower antibody responses to influenza.

    “Some studies have found that human CMV infection in older individuals is associated with increased cardiovascular and all-cause mortality, negative immune risk profile, inflammageing, and lower antibody responses to influenza125–129.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [125] Roberts, E. T., Haan, M. N., Dowd, J. B. & Aiello, A. E. Cytomegalovirus antibody levels, inflammation, and mortality among elderly Latinos over 9 years of follow-up. Am. J. Epidemiol. 172, 363–371 (2010). source

      Not checked in the free run.

    • cites [126] Spyridopoulos, I. et al. CMV seropositivity and T-cell senescence predict increased cardiovascular mortality in octogenarians: results from the Newcastle 85+ study. Aging Cell 15, 389–392 (2016). source

      Not checked in the free run.

    • cites [127] Adriaensen, W. et al. CD4:8 ratio above 5 is associated with all-cause mortality in CMV-seronegative very old women: results from the BELFRAIL study. J. Gerontol. A. Biol. Sci. Med. Sci. 72, 1155–1162 (2017).

      Not checked in the free run.

    • cites [128] Brodin, P. et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37–47 (2015). source

      Not checked in the free run.

    • cites [129] Aiello, A. E., Chiu, Y.-L. & Frasca, D. How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms? GeroScience 39, 261–271 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human CMV infection is a herpesvirus present in a latent state in more than half of the adult population, where intermittent transcription episodes cause antigen reactivation throughout life.

    “Human CMV infection is herpesvirus present in a latent state in more than half of the adult population122, where intermittent transcription episodes cause antigen reactivation throughout the life course.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Cannon, M. J., Schmid, D. S. & Hyde, T. B. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev. Med. Virol. 20, 202–213 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Different mechanisms of inflammageing are likely additive and interconnected, acting in different combinations and with different relevance in selected individuals.

    “These different mechanisms are likely to be additive and interconnected, acting in different combinations and with different relevance in selected individuals.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisenone given

    The possible causes of inflammageing are numerous and very heterogeneous.

    “As explained above, the possible causes of inflammageing are numerous and very heterogeneous (Fig. 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Chronic inflammation in HIV is mediated by depletion of memory CD4+ T cells, resulting in increased permeability in the gut epithelium and translocation of microbial products into the circulation, which causes inflammation.

    “Chronic inflammation in HIV is mediated by depletion of memory CD41+ T cells, resulting in increased permeability in the gut epithelium and translocation of microbial products into the circulation, which causes inflammation136.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136] Brenchley, J. M. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat. Med. 12, 1365–1371 (2006). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Senescent cells are found often in large quantities in atherosclerotic plaques.

    “These two mechanisms are not mutually exclusive; for example, early damage that occurs during vascular endothelial cell inflammation participates in the pathogenesis of atherosclerotic plaques, whereas atherosclerosis itself produces antigens that trigger and sustain an inflammatory response, and senescent cells are found often in large quantities in atherosclerotic plaques.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Patients with HIV are affected by antiretroviral-associated lipodystrophy and visceral obesity that can further contribute to inflammation and cause insulin resistance.

    “Patients with HIV are also affected by antiretroviral-associated lipodystrophy and visceral obesity that can further contribute to inflammation and cause insulin resistance137.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Grunfeld, C. et al. Association of upper trunk and visceral adipose tissue volume with insulin resistance in control and HIV-infected subjects in the FRAM study. J. Acquir. Immune Def. Syndr. 46, 283–290 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Chronic inflammation acts as both a risk factor and a pathogenic mechanism in cardiovascular disease.

    “chronic inflammation is both a risk factor and a pathogenic mechanism in CVD”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisereasoning

    Treatment of these infections can reduce inflammageing and potentially has many long-term beneficial effects beyond immediate local resolution of symptoms.

    “Treatment of these infections can reduce inflammageing and potentially has many long-term beneficial effects beyond immediate local resolution of symptoms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Atherosclerosis begins with damaged endothelium that permits accumulation of oxidized LDL particles in the arterial wall, triggering an unresolved inflammatory response.

    “Atherosclerosis originates from damaged endothelium that allows the accumulation of cholesterol-containing LDL particles in the arterial wall that tend to be oxidized, which triggers an inflammatory response that fails to resolve”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] Libby, P., Ridker, P. M. & Hansson, G. K. Progress and challenges in translating the biology of atherosclerosis. Nature 473, 317–325 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    IL-6 and IL-1 contribute to atherosclerosis and are considered therapeutic targets.

    “IL-6 and IL-1 contribute to atherosclerosis and should be considered to be therapeutic targets”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [158] Ridker, P. M., Hennekens, C. H., Buring, J. E. & Rifai, N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N. Engl. J. Med. 342, 836–843 (2000). source

      Not checked in the free run.

    • cites [163] Ridker, P. M. From C-reactive protein to interleukin-6 to interleukin-1: moving upstream to identify novel targets for atheroprotection. Circ. Res. 118, 145–156 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CRP is a predictive biomarker for cardiovascular disease but is not causally related to atherothrombosis.

    “other mechanistic studies and Mendelian randomization analyses in large populations suggest that CRP is a predictive biomarker that is not causally related to atherothrombosis”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [163] Ridker, P. M. From C-reactive protein to interleukin-6 to interleukin-1: moving upstream to identify novel targets for atheroprotection. Circ. Res. 118, 145–156 (2016). source

      Not checked in the free run.

    • cites [164] Elliott, P. et al. Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA - J. Am. Med. Assoc. 302, 37–48 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Type 2 diabetes is a strong risk factor for cardiovascular disease, and both CVD mortality and the effect of diabetes on CVD risk increase with older age and frailty.

    “Type 2 diabetes is a strong risk factor for CVD, and both CVD mortality and the effect of diabetes on the risk of CVD increase sharply with older age and frailty status”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [174] Cigolle, C. T., Blaum, C. S. & Halter, J. B. Diabetes and cardiovascular disease prevention in older adults. Clin. Geriatr. Med. 25, 607–641 (2009). source

      Not checked in the free run.

    • cites [175] Stout, M. B., Justice, J. N., Nicklas, B. J. & Kirkland, J. L. Physiological aging: Links among adipose tissue dysfunction, diabetes, and frailty. Physiology 32, 9–19 (2017). source

      Not checked in the free run.

    • cites [176] Halter, J. B. et al. Diabetes and cardiovascular disease in older adults: current status and future directions. Diabetes 63, 2578–2589 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High doses of infliximab did not improve and even worsened moderate-to-severe congestive heart failure.

    “high doses of infliximab, a TNF antagonist, did not improve and even worsened moderate-to-severe congestive heart failure”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [194] Chung, E. S. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure. Circulation 107, 3133–3140 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In congestive heart failure, pro-inflammatory cytokines TNF, IL-6, and IL-1 are markedly elevated, and TNF level is a negative prognostic factor.

    “in patients with congestive heart failure, the levels of pro-inflammatory cytokines, especially TNF, IL-6, and IL-1, are markedly elevated, and the TNF level is a negative prognostic factor”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [190] Anker, S. D. Inflammatory mediators in chronic heart failure: an overview. Heart 90, 464–470 (2004). source

      Not checked in the free run.

    • cites [191] Levine, B., Kalman, J., Mayer, L., Fillit, H. M. & Packer, M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N. Engl. J. Med. 323, 236–241 (1990). source

      Not checked in the free run.

    • cites [192] Torre-Amione, G. et al. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: A report from the studies of left ventricular dysfunction (SOLVD). J. Am. Coll. Cardiol. 27, 1201–1206 (1996). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    CVD and frailty can be viewed as diseases arising from similar causal mechanisms that mutually accelerate their clinical course through vicious cycles.

    “CVD and frailty can be viewed as diseases arising from similar causal mechanisms, mutually accelerating their clinical course by vicious cycles”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Strong evidence from multiple large observational studies indicates that CVD is a risk factor for frailty and that frail patients are more likely to develop CVD than non-frail individuals.

    “Strong evidence from multiple, large, observational studies indicates that the presence of CVD is a risk factor for frailty and that patients with frailty are more likely to develop CVD than those who are not frail”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [201] Woods, N. F. et al. Frailty: emergence and consequences in women aged 65 and older in the Women’s Health Initiative Observational Study. J. Am. Geriatr. Soc. 53, 1321–1330 (2005). source

      Not checked in the free run.

    • cites [202] Corti, M. C., Salive, M. E. & Guralnik, J. M. Serum albumin and physical function as predictors of coronary heart disease mortality and incidence in older persons. Clin. J. Epidemiol. 49, 519–526 (1996). source

      Not checked in the free run.

    • cites [203] McDermott, M. M. et al. Decline in functional performance predicts later increased mobility loss and mortality in peripheral arterial disease. J. Am. Coll. Cardiol. 57, 962–970 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Higher levels of inflammatory markers in blood are associated with greater loss of muscle mass and strength, accelerated loss of mobility, lower-extremity performance and physical activity, and depression in older individuals.

    “higher levels of inflammatory markers in blood are associated with a greater loss of muscle mass and strength, accelerated loss of mobility, lower-extremity performance and physical activity, and depression in older individuals”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [224] Schlegel, T. F., Hawkins, R. J., Lewis, C. W., Motta, T. & Turner, A. S. The effects of augmentation with swine small intestine submucosa on tendon healing under tension: histologic and mechanical evaluations in sheep. Am. J. Sports Med. 34, 275–280 (2006). source

      Not checked in the free run.

    • cites [225] Ferrucci, L. et al. Change in muscle strength explains accelerated decline of physical function in older women with high interleukin-6 serum levels. J. Am. Geriatr. Soc. 50, 1947–1954 (2002). source

      Not checked in the free run.

    • cites [226] Visser, M. et al. Relationship of interleukin-6 and tumor necrosis factor-α with muscle nass and muscle strength in elderly men and women: the Health ABC Study. J. Gerontol. A Biol. Sci. Med. Sci. 57, M326–M332 (2002). source

      Not checked in the free run.

    • cites [227] Cesari, M. et al. Inflammatory markers and physical performance in older persons: the InCHIANTI Study. J. Gerontol. A Biol. Sci. Med. Sci. 59, M242–M248 (2004). source

      Not checked in the free run.

    • cites [228] Santos-Eggimann, B., Cuénoud, P., Spagnoli, J. & Junod, J. Prevalence of frailty in middle-aged and older community-dwelling Europeans living in 10 countries. J. Gerontol. A Biol. Sci. Med. Sci. 64, 675–681 (2009). source

      Not checked in the free run.

    • Rests on an assumption: Blood levels of inflammatory markers such as IL-6 and CRP adequately reflect chronic inflammation (inflammageing).

  • May combine two claims.

    Premisecitation

    Both higher baseline levels and increasing accumulation rates of IL-6 predict accelerated longitudinal accumulation of multiple chronic diseases in older individuals.

    “both higher baseline levels and increasing accumulation rates of IL-6 predict accelerated longitudinal accumulation of multiple chronic diseases in older individuals”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Fabbri, E. et al. Aging and the burden of multimorbidity: associations with inflammatory and anabolic hormonal biomarkers. J. Gerontol. A. Biol. Sci. Med. Sci. 70, 63–70 (2015). source

      Not checked in the free run.

    • Rests on an assumption: Blood levels of inflammatory markers such as IL-6 and CRP adequately reflect chronic inflammation (inflammageing).

  • May combine two claims.

    Premisereasoning

    Most patients with frailty have chronic inflammation, especially those with sarcopenia.

    “most patients with frailty have chronic inflammation, especially those who are affected by sarcopenia”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [207] Walston, J. et al. Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study. Arch. Intern. Med. 162, 2333–2341 (2002). source

      Not checked in the free run.

    • cites [232] Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L. & Woodhouse, K. W. Inflammation and frailty measures in older people. J. Cell Mol. Med. 13, 3103–3109 (2009). source

      Not checked in the free run.

    • cites [233] Newman, A. B. et al. Weight change in old age and its association with mortality. J. Am. Geriatr. Soc. 49, 1309–1318 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A randomized controlled trial in Indonesia found that metformin improves gait speed but not handgrip strength in nondiabetic, pre-frail, older individuals.

    “An RCT conducted in Indonesia revealed that metformin improves gait speed, but not handgrip strength, in nondiabetic, pre-frail, older individuals”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [255] Laksmi, P. W., Setiati, S., Tamin, T. Z. & Soewondo, P. Effect of metformin on handgrip strength, gait speed, myostatin serum level, and health-related quality of life: a double blind randomized controlled trial among non-diabetic pre-frail elderly patients. Acta Med. Indones. 49, 118–127 (2017).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Aspirin is effective in the treatment of acute myocardial infarction and in secondary prevention of cardiovascular disease.

    “Aspirin, a potent anti-inflammatory molecule, is effective in the treatment of acute myocardial infarction and in secondary prevention of CVD”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [251] Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324, 71–86 (2002). source

      Not checked in the free run.

    • cites [252] De Caterina, R. [Aspirin for primary cardiovascular disease prevention - an update]. G. Ital. Cardiol. 18, 1–6 (2017).

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Although strong evidence shows that targeting inflammation can reduce the risk of CVD, no definitive evidence exists that reducing inflammation can prevent or modify the progression of multimorbidity with frailty or sarcopenia.

    “although strong evidence shows that targeting inflammation can reduce the risk of CVD, no definitive evidence exists that reducing inflammation can prevent or modify the progression of multimorbidity with frailty or sarcopenia”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Calorie restriction is the most powerful life-extension intervention in most animal models and is associated with reduced inflammatory biomarkers.

    “calorie restriction is the most powerful life-extension intervention in most animal models and is associated with reduced inflammatory biomarkers”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [261] Barzilai, N., Huffman, D. M., Muzumdar, R. H. & Bartke, A. The critical role of metabolic pathways in aging. Diabetes 61, 1315–1322 (2012). source

      Not checked in the free run.

    • cites [262] Fontana, L. Neuroendocrine factors in the regulation of inflammation: excessive adiposity and calorie restriction. Exp. Gerontol. 44, 41–45 (2009). source

      Not checked in the free run.

    • Rests on an assumption: Findings from animal models about longevity interventions and inflammation can be extrapolated to humans.

  • May combine two claims.

    Premisecitation

    Dietary restriction significantly reduces the risk of CVD in humans and is associated with beneficial changes in arterial walls in animal models.

    “dietary restriction significantly reduces the risk of CVD in humans, and in animal models, dietary restriction is associated with numerous beneficial changes in arterial walls”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [264] LaRocca, T. J., Martens, C. R. & Seals, D. R. Nutrition and other lifestyle influences on arterial aging. Ageing Res. Rev. 39, 106–119 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a large observational study of US veterans with type 2 diabetes, metformin reduced the risk of multiple age-related diseases, including cardiovascular diseases, cancer, depression, and frailty-related diseases.

    “treatment with metformin reduced the risk of multiple age-related diseases, including CVDs, cancer, depression, and frailty-related diseases”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [254] Wang, C.-P., Lorenzo, C., Habib, S. L., Jo, B. & Espinoza, S. E. Differential effects of metformin on age related comorbidities in older men with type 2 diabetes. J. Diabetes Complications 31, 679–686 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inflammation is associated with anabolic resistance in muscle, caused partly by inhibition of perfusion adjustment to anabolic stimuli and partly by inhibition of IGF1 production and signalling.

    “inflammation is associated with anabolic resistance in muscle, which is caused partly by inhibition of the perfusion adjustment to anabolic stimuli and partly by inhibition of IGF1 production and signalling”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [236] Barbieri, M. et al. Chronic inflammation and the effect of IGF-I on muscle strength and power in older persons. Am. J. Physiol. Metab. 284, E481–E487 (2003).

      Not checked in the free run.

    • cites [237] Cappola, A. R. et al. Insulin-like growth factor I and interleukin-6 contribute synergistically to disability and mortality in older women. J. Clin. Endocrinol. Metab. 88, 2019–2025 (2003). source

      Not checked in the free run.

    • cites [238] Timmerman, K. L. et al. Pharmacological vasodilation improves insulin-stimulated muscle protein anabolism but not glucose utilization in older adults. Diabetes 59, 2764–2771 (2010). source

      Not checked in the free run.

    • cites [239] Moaddel, R. et al. Plasma biomarkers of poor muscle quality in older men and women from the Baltimore Longitudinal Study of Aging. J. Gerontol. A Biol. Sci. Med. Sci. 71, 1266–1272 (2016). source

      Not checked in the free run.

    • cites [240] Fichtlscherer, S. et al. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation 102, 1000–1006 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clearance of senescent cells by genetic engineering or senolytic drugs is associated with reduced circulating pro-inflammatory markers, increased lifespan, and delayed frailty-related phenotypes in mice.

    “the clearance of senescent cells by either genetic engineering or the administration of senolytic drugs has been associated with reduced circulating levels of pro-inflammatory markers, increased lifespan, and delayed frailty-related phenotypes in mice”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [111] Baker, D. J. et al. Clearance of p16 Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). source

      Not checked in the free run.

    • cites [112] Baker, D. J. et al. Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). source

      Not checked in the free run.

    • Rests on an assumption: Findings from animal models about longevity interventions and inflammation can be extrapolated to humans.

  • May combine two claims.

    Interpretationreasoning

    Interventions that target fundamental mechanisms of ageing affect general susceptibility to CVD and other age-related diseases and prevent frailty and disability in older individuals.

    “interventions that target some of the fundamental mechanisms of ageing affect the general susceptibility to CVD, as well as other age-related diseases, and prevent frailty and disability in older individuals”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from animal models about longevity interventions and inflammation can be extrapolated to humans.

  • May combine two claims.

    Premisecitation

    Chronic inflammation causes anaemia via direct inhibition of iron absorption and recycling as well as interference with erythropoietin production and signalling.

    “Chronic inflammation causes anaemia via direct inhibition of iron absorption and recycling as well as interference with erythropoietin production and signalling”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Ferrucci, L. et al. Proinflammatory state, hepcidin, and anemia in older persons. Blood 115, 3810–3816 (2010). source

      Not checked in the free run.

    • cites [280] Ferrucci, L. et al. Proinflammatory state and circulating erythropoietin in persons with and without anemia. Am. J. Med. 118, 1288.e11–1288.e19 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Studies in vitro and in animal models suggest that inflammation, especially IL-1β and IFNα, inhibits neurogenesis and reduces exercise-induced neurogenesis.

    “Studies conducted both in vitro and in animal models suggest that inflammation in general, and IL-1β and IFNα in particular, inhibit neurogenesis and reduce the magnitude of neurogenesis that is normally induced by exercise”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [288] Lezi, E., Burns, J. M. & Swerdlow, R. H. Effect of high-intensity exercise on aged mouse brain mitochondria, neurogenesis, and inflammation. Neurobiol. Aging 35, 2574–2583 (2014). source

      Not checked in the free run.

    • cites [289] Borsini, A. et al. Interferon-α reduces human hippocampal neurogenesis and increases apoptosis via activation of distinct STAT1-dependent mechanisms. Int. J. Neuropsychopharmacol. 21, 187–200 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pro-inflammatory cytokines, including IL-1β, IL-6, IL-11, IL-15, IL-17, and TNF, stimulate bone resorption and almost certainly contribute to osteoporosis.

    “Pro-inflammatory cytokines — including IL-1β, IL-6, IL-11, IL-15, IL-17, and TNF — stimulate bone resorption and almost certainly contribute to osteoporosis”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [285] Abdelmagid, S. M., Barbe, M. F. & Safadi, F. F. Role of inflammation in the aging bones. Life Sci. 123, 25–34 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    In older individuals, inflammation remains chronically activated either because of continued stress from the inflammation source or because of a primary immune dysregulation.

    “in older individuals, inflammation remains chronically activated, either because of continued stress from the inflammation source or because of a primary immune dysregulation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Modulating inflammageing is a promising strategy to prevent CVD and to slow the decline of health that occurs with ageing.

    “modulating inflammageing is a promising strategy not only to prevent CVD but also to slow the decline of health that occurs with ageing”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from animal models about longevity interventions and inflammation can be extrapolated to humans.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    In the absence of macromolecular and organellar recycling, the accumulation of damage can reach a critical threshold, causing severe functional consequences that confer the clinical syndrome of frailty.

    “In the absence of macromolecular and organellar recycling, the accumulation of damage can reach a critical threshold, thereby causing severe functional consequences that become difficult or impossible to reverse, conferring the clinical syndrome of frailty”
    Quote in the paperNot a substantial claim
74 of 74

  • The paper relies on this without support.

    Blood levels of inflammatory markers adequately reflect inflammageing and its biological effects.

    “Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death.”
    “The pro-inflammatory state is characterized by high circulating levels of pro-inflammatory markers, including IL-1, IL-1 receptor antagonist protein (IL-1RN), IL-6, IL-8, IL-13, IL-18, C-reactive protein (CRP), IFNα and IFNβ, transforming growth factor-β (TGFβ), tumour necrosis factor (TNF) and its soluble receptors (TNF receptor superfamily members 1A and 1B), and serum amyloid A.”

  • The paper relies on this without support.

    Findings from animal models about longevity interventions and inflammation can be extrapolated to humans.

    “Many interventions that increase longevity in animal models cause a reduction in inflammatory markers”
    “These examples suggest that interventions that target some of the fundamental mechanisms of ageing affect the general susceptibility to CVD, as well as other age-related diseases, and prevent frailty and disability in older individuals”

  • The paper relies on this without support.

    Blood levels of inflammatory markers such as IL-6 and CRP adequately reflect chronic inflammation (inflammageing).

    “high blood levels of pro-inflammatory markers, including high-sensitivity CRP assay and IL-6, predict the risk of cardiovascular disease in both middle-aged and older adults”
    “both higher baseline levels and increasing accumulation rates of IL-6 predict accelerated longitudinal accumulation of multiple chronic diseases in older individuals”
3 of 3

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?

  • Ageing is characterised by increased production of ROS due to mitochondrial dysfunction and inflammageing, alongside reduced antioxidant capacity.

    “Ageing is characterised by increased production of reactive oxygen species (ROS) due to mitochondrial dysfunction and inflammageing, alongside reduced antioxidant capacity [253,254,255].”

    From Dietary Nitrate-Rich Vegetables as Natural Modulators of Health: Mechanisms and Benefits in Ageing Populations (2026) · cites this paper as [254]

    In “Impaired recycling and elimination of degraded cellular material” (page unavailable), the paper says damaged mitochondria produce ROS that can trigger inflammation. “Inflammageing is a pillar of geroscience” (page unavailable) also reports that inflammatory cytokines can cause mitochondrial dysfunction. These passages support a connection among mitochondrial dysfunction, ROS and inflammageing, but do not establish the claimed age-related increase in ROS production or reduced antioxidant capacity. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • 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 [4]

  • Increased levels of inflammatory mediators, mostly IL-1, IL-6, TNF-α, and its receptors, are detected in all elderly individuals.

    “Although increased levels of inflammatory mediators (mostly IL-1, IL-6, TNF-α, and its receptors) are detected in all elderly individuals, higher levels of these biomarkers are associated with increased risk for many chronic conditions, including dementia, disability, and physical frailty.”

    From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [4]

  • Inflammaging is implicated in the pathogenesis of many age-associated chronic diseases and in loss of physical and cognitive function.

    “Inflammaging has been implicated in the pathogenesis of many age-associated chronic diseases as well as loss of physical and cognitive function.”

    From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [4]

  • Higher levels of inflammatory biomarkers are associated with increased risk for many chronic conditions, including dementia, disability, and physical frailty.

    “higher levels of these biomarkers are associated with increased risk for many chronic conditions, including dementia, disability, and physical frailty.”

    From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [4]

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 1

  1. De Caterina, R. [Aspirin for primary cardiovascular disease prevention - an update]. G. Ital. Cardiol. 18, 1–6 (2017).

Cited by

Sorted by citations

Related

Authors
Ferrucci, L., & Fabbri, E.
Affiliations
  • National Institutes of Health (US)
  • University of Bologna (IT)
Corresponding author
Ferrucci, Luigi
ORCID
Venue
Nature Reviews Cardiology
Publisher
Springer Science and Business Media LLC
Published
2018-07-31
Volume
15
Issue
9
Pages
505-522
ISSN
  • 1759-5002 (ISSN-L)
  • 1759-5010
DOI
10.1038/s41569-018-0064-2
PMC
PMC6146930
OpenAlex
W2885738092
Cited by
3,690
References
316
Citations by year
2026: 686 · 2025: 641 · 2024: 615 · 2023: 538 · 2022: 453 · 2021: 375 · 2020: 263 · 2019: 107 · 2018: 9 · 2016: 1
FWCI
20.98
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Cardiology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
Funders
  • National Institutes of Health (Z99 AG999999)
  • National Institute on Aging
Topics
  • Health Sciences › Medicine › Geriatrics and Gerontology › Frailty in Older Adults
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
inflammaging, chronic inflammation, aging, cardiovascular disease, frailty, multimorbidity, cellular senescence, NLRP3 inflammasome, intestinal permeability, gut microbiota, mitochondrial dysfunction, oxidative stress, immune dysregulation, chronic infection, sarcopenia, dementia, depression, chronic kidney disease, diabetes mellitus, cancer, anti-inflammatory therapy
MeSH terms
Frailty, Adult, Aged, Aged, 80 and over, Aging, Animals, Cardiovascular Diseases, Chronic Disease, Humans, Inflammation, Middle Aged, Frail Elderly, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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