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

In the paper

“The number of B lymphocytes and macrophages in visceral adipose tissue from obese individuals is also increased and is correlated with BMI55.”

What the sources say

• Partly supported

  The Adipose Tissue Inflammation section says B2 cells accumulate in adipose tissue after a high-fat diet in mice and describes macrophage recruitment to expanding adipose tissue. It does not establish that both cell types are increased in visceral adipose tissue of obese humans or that their numbers correlate with BMI; the paper’s BMI discussion concerns telomere length. (LLM, conf=0.85)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Not checked yetcites [67] Biagi, E. et al. Gut microbiota and extreme longevity. Curr. Biol. 26, 1480–1485 (2016). source
• Partly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  cites [77] Barrios, C. et al. Gut-microbiota-metabolite axis in early renal function decline. PLoS ONE 10, e0134311 (2015). sourceExperimental — accuracy not yet measured
• Not checked yetcites [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
• Partly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [20] Hodes, R. J. et al. Disease drivers of aging. Ann. NY Acad. Sci. 1386, 45–68 (2016). source

In the paper

“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.”

In the paper

“Ageing is associated with immune dysregulation, of which the most evident characteristics are high blood levels of pro-inflammatory immunogenic stimulations3,4.”

What the sources say

• Not checked yetcites [3] Ferrucci, L. et al. Proinflammatory state, hepcidin, and anemia in older persons. Blood 115, 3810–3816 (2010). source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“Multiple SNPs in the CRP gene are associated with higher CRP levels and increased risk of myocardial infarction and CVD-related death38.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [40] Pilling, L. C. et al. Gene expression markers of age-related inflammation in two human cohorts. Exp. Gerontol. 70, 37–45 (2015). source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [54] Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–189 (2011). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [49] Dluzen, D. F., Noren Hooten, N. & Evans, M. K. Extracellular. RNA in aging. WIREs RNA. https://doi.org/10.1002/wrna.1385 (2017). source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“Activated monocytes that give rise to M1 and M2 macrophages produce even more inflammatory compounds that probably appear in the circulation57.”

What the sources say

• Not checked yetcites [57] Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003). source

In the paper

“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.”

What the sources say

• Not checked yetcites [69] Rampelli, S. et al. Functional metagenomic profiling of intestinal microbiome in extreme ageing. Aging 5, 902–912 (2013). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [66] Mariat, D. et al. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol. 9, 123 (2009). source
• Not checked yetcites [67] Biagi, E. et al. Gut microbiota and extreme longevity. Curr. Biol. 26, 1480–1485 (2016). source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [75] O’Toole, P. W. & Jeffery, I. B. Gut microbiota and aging. Science 350, 1214–1215 (2015). source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [66] Mariat, D. et al. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol. 9, 123 (2009). source
• Not checked yetcites [67] Biagi, E. et al. Gut microbiota and extreme longevity. Curr. Biol. 26, 1480–1485 (2016). source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [70] Biagi, E. et al. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS ONE 5, e10667 (2010). source

In the paper

“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.”

What the sources say

• Not checked yetcites [90] Bernardes de Jesus, B. & Blasco, M. A. Assessing cell and organ senescence biomarkers. Circ. Res. 111, 97–109 (2012). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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).

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [108] Klenerman, P. & Oxenius, A. T cell responses to cytomegalovirus. Nat. Rev. Immunol. 16, 367–377 (2016). source
• Not checked yetcites [109] Sansoni, P. et al. New advances in CMV and immunosenescence. Exp. Gerontol. 55, 54–62 (2014). source
• Not checked yetcites [110] Fulop, T., Larbi, A. & Pawelec, G. Human T cell aging and the impact of persistent viral infections. Front. Immunol. 4, 271 (2013). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [112] Baker, D. J. et al. Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [117] Kepp, O., Galluzzi, L. & Kroemer, G. Mitochondrial control of the NLRP3 inflammasome. Nat. Immunol. 12, 199–200 (2011). source
• Not checked yetcites [118] Ferrucci, L. et al. The origins of age-related proinflammatory state. Blood 105, 2294–2299 (2005). source

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“As explained above, the possible causes of inflammageing are numerous and very heterogeneous (Fig. 1).”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“Patients with HIV are also affected by antiretroviral-associated lipodystrophy and visceral obesity that can further contribute to inflammation and cause insulin resistance137.”

What the sources say

• Not checked yetcites [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

In the paper

“chronic inflammation is both a risk factor and a pathogenic mechanism in CVD”

In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites [144] Libby, P., Ridker, P. M. & Hansson, G. K. Progress and challenges in translating the biology of atherosclerosis. Nature 473, 317–325 (2011). source

In the paper

“IL-6 and IL-1 contribute to atherosclerosis and should be considered to be therapeutic targets”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“other mechanistic studies and Mendelian randomization analyses in large populations suggest that CRP is a predictive biomarker that is not causally related to atherothrombosis”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [176] Halter, J. B. et al. Diabetes and cardiovascular disease in older adults: current status and future directions. Diabetes 63, 2578–2589 (2014). source

In the paper

“high doses of infliximab, a TNF antagonist, did not improve and even worsened moderate-to-severe congestive heart failure”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [190] Anker, S. D. Inflammatory mediators in chronic heart failure: an overview. Heart 90, 464–470 (2004). source
• Not checked yetcites [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 yetcites [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

In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“most patients with frailty have chronic inflammation, especially those who are affected by sarcopenia”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“An RCT conducted in Indonesia revealed that metformin improves gait speed, but not handgrip strength, in nondiabetic, pre-frail, older individuals”

What the sources say

• Not checked yetcites [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).

In the paper

“Aspirin, a potent anti-inflammatory molecule, is effective in the treatment of acute myocardial infarction and in secondary prevention of CVD”

What the sources say

• Not checked yetcites [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 yetcites [252] De Caterina, R. [Aspirin for primary cardiovascular disease prevention - an update]. G. Ital. Cardiol. 18, 1–6 (2017).

In the paper

“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”

In the paper

“calorie restriction is the most powerful life-extension intervention in most animal models and is associated with reduced inflammatory biomarkers”

What the sources say

• Not checked yetcites [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 yetcites [262] Fontana, L. Neuroendocrine factors in the regulation of inflammation: excessive adiposity and calorie restriction. Exp. Gerontol. 44, 41–45 (2009). source

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“treatment with metformin reduced the risk of multiple age-related diseases, including CVDs, cancer, depression, and frailty-related diseases”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [112] Baker, D. J. et al. Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). source

In the paper

“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”

In the paper

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

What the sources say

• Not checked yetcites [3] Ferrucci, L. et al. Proinflammatory state, hepcidin, and anemia in older persons. Blood 115, 3810–3816 (2010). source
• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [285] Abdelmagid, S. M., Barbe, M. F. & Safadi, F. F. Role of inflammation in the aging bones. Life Sci. 123, 25–34 (2015). source

In the paper

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

In the paper

“modulating inflammageing is a promising strategy not only to prevent CVD but also to slow the decline of health that occurs with ageing”

In the paper

“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”