CoChat
Sign Up
Cited by 62Genetics, Aging, and Longevity in Model OrganismsCytokine Signaling Pathways and InteractionsAdipokines, Inflammation, and Metabolic Diseases

Inflammaging: Age and Systemic, Cellular, and Nuclear Inflammatory Biology in Older Adults

Open access
Piber, Dominique, Olmstead, Richard, Cho, Joshua Hyong-Jin, Witarama, Tuff, Perez, Christian, Dietz, Nicholas, Seeman, Teresa E, Breen, Elizabeth C +2 more·2019·The Journals of Gerontology: Series A
DOI 10.1093/gerona/glz130PMC PMC6777092
Open this paper in CoChat — free accountOpen PDF

Abstract

Systemic inflammation is associated with increasing age. Yet, there are limited data about the association between age and systemic inflammation within older adults, and whether older age is also associated with cellular and nuclear signaling markers of inflammation. In community-dwelling older adults (N = 262, 60–88 years), systemic levels of C-reactive protein, interleukin-6, and soluble tumor necrosis factor receptor II; levels of toll-like receptor-4–stimulated monocytic production of interleukin-6 and tumor necrosis factor α; and resting nuclear levels of activated nuclear factor kappa B and signal transducer and activator of transcription (STAT1, STAT3, STAT5) were evaluated. Adjusting for demographic and clinical factors, multivariate linear regression tested the association between age and each inflammatory marker. Age was positively associated with increased levels of interleukin-6 and soluble tumor necrosis factor receptor II (p’s < .05) and with increases in STAT1, STAT3, and STAT5 activation (p’s < .05). However, no relationship was found between age and C-reactive protein, toll-like receptor-4–stimulated interleukin-6/tumor necrosis factor alpha α production, or nuclear factor kappa B. Within a community-dwelling sample of older adults, older age is associated with increases in STAT activation, along with increases of systemic inflammatory cytokines. In older adults, heterogeneity in age-related increases in inflammatory disease risk may be related to individual variability in inflammation.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/gerona/glz130

Cites

7 of 7 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 54

  1. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its po- tential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014;69(Suppl. 1):S4-S9. doi:10.1093/gerona/glu057 · DOI · Paper page
  2. Franceschi C, Bonafè M, Valensin S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244-254. doi:10.1111/j.1749-6632.2000.tb06651.x · DOI · Paper page
  3. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation. 2003;107:391- 397. doi:10.1161/01.CIR.0000055014.62083. · DOI
  4. Vasto S, Carruba G, Lio D, et al. Inflammation, ageing and cancer. Mech Ageing Dev. 2009;130:40-45. doi:10.1016/j.mad.2008.06.003 · DOI
  5. Pierce BL, Ballard-Barbash R, Bernstein L, et al. Elevated biomarkers of in- flammation are associated with reduced survival among breast cancer pa- tients. J Clin Oncol. 2009;27:3437-3444. doi:10.1200/JCO.2008.18.9068 · DOI
  6. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436-444. doi:10.1038/nature07205 · DOI · Paper page
  7. Volpato S, Guralnik JM, Ferrucci L, et al. Cardiovascular disease, inter- leukin-6, and risk of mortality in older women: the women's health and aging study. Circulation. 2001;103:947-953. doi:10.1161/01. CIR.103.7.947 · DOI
  8. Harris TB, Ferrucci L, Tracy RP, et al. Associations of elevated inter- leukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med. 1999;106:506-512. doi:10.1016/S0002-9343(99)00066-2 · DOI · Paper page
  9. Ershler WB, Keller ET. Age-associated increased interleukin-6 gene ex- pression, late-life diseases, and frailty. Annu Rev Med. 2000;51:245-270. doi:10.1146/annurev.med.51.1.245 · DOI · Paper page
  10. Gerli R, Monti D, Bistoni O, et al. Chemokines, sTNF-Rs and sCD30 serum levels in healthy aged people and centenarians. Mech Ageing Dev. 2000;121:37-46. doi:10.1016/S0047-6374(00)00195-0 · DOI · Paper page
  11. Murasko DM, Nelson BJ, Matour D, Goonewardene IM, Kaye D. Heterogeneity of changes in lymphoproliferative ability with increasing age. Exp Gerontol. 1991;26:269-279.
  12. Salminen A, Huuskonen J, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T. Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflammaging. Ageing Res Rev. 2008;7:83-105. doi:10.1016/j.arr.2007.09.002 · DOI · Paper page
  13. O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and thera- peutic intervention. Annu Rev Med. 2015;66:311-328. doi:10.1146/ annurev-med-051113-024537 · DOI
  14. Cho JH, Olmstead R, Choi H, Carrillo C, Seeman TE, Irwin MR. Associations of objective versus subjective social isolation with sleep dis- turbance, depression, and fatigue in community-dwelling older adults. Aging & Ment Health. 2018:1-9. doi:10.1080/13607863.2018.1481928 · DOI
  15. Von Korff M, Wagner EH, Saunders K. A chronic disease score from automated pharmacy data. J Clin Epidemiol. 1992;45:197-203. doi:10.1016/0895-4356(92)90016-G · DOI
  16. Irwin MR, Wang M, Campomayor CO, Collado-Hidalgo A, Cole S. Sleep deprivation and activation of morning levels of cellular and gen- omic markers of inflammation. Arch Intern Med. 2006;166:1756-1762. doi:10.1001/archinte.166.16.1756 · DOI · Paper page
  17. Irwin MR, Witarama T, Caudill M, Olmstead R, Breen EC. Sleep loss activates cellular inflammation and signal transducer and activator of transcription (STAT) family proteins in humans. Brain Behav Immun. 2015;47:86-92. doi:10.1016/j.bbi.2014.09.017 · DOI
  18. Glejser H. A new test for heteroskedasticity. J Am Stat Assoc. 1969;64:315-323.
  19. Woloshin S, Schwartz LM. Distribution of C-reactive protein values in the United States. N Engl J Med. 2005;352:1611-1613. doi:10.1056/ NEJM200504143521525 · DOI
  20. Cho HJ, Kivimäki M, Bower JE, Irwin MR. Association of C-reactive protein and interleukin-6 with new-onset fatigue in the Whitehall II pro- spective cohort study. Psychol Med. 2013;43:1773-1783. doi:10.1017/ S0033291712002437 · DOI
  21. Marcos-Pérez D, Sánchez-Flores M, Maseda A, et al. Frailty in older adults is associated with plasma concentrations of inflammatory mediators but not with lymphocyte subpopulations. Front Immunol. 2018;9:1056. doi:10.3389/fimmu.2018.01056 · DOI
  22. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA. 1999;282:2131-2135. doi:10.1001/jama.282.22.2131 · DOI · Paper page
  23. Chazaud B, Mouchiroud G. Inflamm-aging: STAT3 signaling pushes muscle stem cells off balance. Cell Stem Cell. 2014;15:401-402. doi:10.1016/j.stem.2014.09.010 · DOI
  24. Albright JW, Bream JH, Bere EW, Young HA, Winkler-Pickett R, Ortaldo JR. Aging of innate immunity: functional comparisons of NK/LAK cells obtained from bulk cultures of young and aged mouse spleen cells in high concentrations of interleukin-2. Exp Gerontology. 2004;39:73-82. doi:10.1016/j.exger.2003.09.017 · DOI
  25. McLoughlin RM, Jenkins BJ, Grail D, et al. IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation. Proc Natl Acad Sci USA. 2005;102:9589-9594. doi:10.1073/pnas.0501794102 · DOI
  26. Fielding CA, McLoughlin RM, McLeod L, et al. IL-6 regulates neu- trophil trafficking during acute inflammation via STAT3. J Immunol. 2008;181:2189-2195. doi:10.4049/jimmunol.181.3.2189 · DOI
  27. Takeda K, Clausen BE, Kaisho T, et al. Enhanced Th1 activity and de- velopment of chronic enterocolitis in mice devoid of Stat3 in macro- phages and neutrophils. Immunity. 1999;10:39-49. doi:10.1016/ S1074-7613(00)80005-9 · DOI · Paper page
  28. Majoros A, Platanitis E, Szappanos D, et al. Response to interferons and antibacterial innate immunity in the absence of tyrosine-phosphorylated STAT1. EMBO Rep. 2016;17:367-382. doi:10.15252/embr.201540726 · DOI
  29. Durbin JE, Hackenmiller R, Simon MC, Levy DE. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell. 1996;84:443-450. doi:10.1016/S0092-8674(00)81289-1 · DOI
  30. Shuai K, Liao J, Song MM. Enhancement of antiproliferative activity of gamma interferon by the specific inhibition of tyrosine dephosphorylation of Stat1. Mol Cell Biol. 1996;16:4932-4941. doi:10.1128/mcb.16.9.4932 · DOI
  31. Lin JX, Leonard WJ. The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene. 2000;19:2566-2576. doi:10.1038/ sj.onc.1203523 · DOI
  32. Imada K, Bloom ET, Nakajima H, et al. Stat5b is essential for nat- ural killer cell-mediated proliferation and cytolytic activity. J Exp Med. 1998;188:2067-2074. doi:10.1084/jem.188.11.2067 · DOI
  33. Nakajima H, Liu XW, Wynshaw-Boris A, et al. An indirect effect of Stat5a in IL-2-induced proliferation: a critical role for Stat5a in IL-2-mediated IL-2 receptor alpha chain induction. Immunity. 1997;7:691-701. doi:10.1016/S1074-7613(00)80389-1 · DOI
  34. Vogel TP, Milner JD, Cooper MA. The Ying and Yang of STAT3 in human disease. J Clin Immunol. 2015;35:615-623. doi:10.1007/ s10875-015-0187-8 · DOI
  35. Salminen A, Kauppinen A, Kaarniranta K. Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal. 2012;24:835-845. doi:10.1016/j. cellsig.2011.12.006 · DOI · Paper page
  36. Gupta S, Bi R, Kim C, Chiplunkar S, Yel L, Gollapudi S. Role of NF-kappaB signaling pathway in increased tumor necrosis factor-alpha- induced apoptosis of lymphocytes in aged humans. Cell Death Differ. 2005;12:177-183. doi:10.1038/sj.cdd.4401557 · DOI
  37. Bektas A, Zhang Y, Lehmann E, et al. Age-associated changes in basal NF-κB function in human CD4+ T lymphocytes via dysregulation of PI3 kinase. Aging (Albany, NY). 2014;6:957-974. doi:10.18632/aging.100705 · DOI
  38. Bektas A, Schurman SH, Sen R, Ferrucci L. Human T cell immunosenescence and inflammation in aging. J Leukoc Biol. 2017;102:977-988. doi:10.1189/jlb.3RI0716-335R · DOI
  39. Bektas A, Schurman SH, Sen R, Ferrucci L. Aging, inflammation and the environment. Exp Gerontol. 2018;105:10-18. doi:10.1016/j. exger.2017.12.015 · DOI
  40. Harries LW, Hernandez D, Henley W, et al. Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing. Aging Cell. 2011;10:868-878. doi:10.1111/j.1474-9726.2011.00726.x · DOI
  41. Holly AC, Melzer D, Pilling LC, et al. Towards a gene expression bio- marker set for human biological age. Aging Cell. 2013;12:324-326. doi:10.1111/acel.12044 · DOI
  42. Jylhävä J, Raitanen J, Marttila S, Hervonen A, Jylhä M, Hurme M. Identification of a prognostic signature for old-age mortality by integrating genome-wide transcriptomic data with the conventional predictors: the Vitality 90+ Study. BMC Med Genomics. 2014;7:54. doi:10.1186/1755-8794-7-54 · DOI
  43. Reynolds LM, Ding J, Taylor JR, et al. Transcriptomic profiles of aging in purified human immune cells. BMC Genomics. 2015;16:333. doi:10.1186/ s12864-015-1522-4 · DOI · Paper page
  44. de Magalhães JP, Curado J, Church GM. Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics. 2009;25:875-881. doi:10.1093/bioinformatics/btp073 · DOI · Paper page
  45. Carroll JE, Carrillo C, Olmstead R, et al. Sleep deprivation and diver- gent toll-like receptor-4 activation of cellular inflammation in aging. Sleep. 2015;38:205-211. doi:10.5665/sleep.4398 · DOI · Paper page
  46. Giuliani N, Sansoni P, Girasole G, et al. Serum interleukin-6, sol- uble interleukin-6 receptor and soluble gp130 exhibit different patterns of age-and menopause-related changes. Exp Gerontol. 2001;36:547-557.
  47. Paik JK, Chae JS, Kang R, Kwon N, Lee SH, Lee JH. Effect of age on atherogenicity of LDL and inflammatory markers in healthy women. Nutr Metab Cardiovasc Dis. 2013;23:967-972. doi:10.1016/j. numecd.2012.08.002 · DOI
  48. Hager K, Machein U, Krieger S, Platt D, Seefried G, Bauer J. Interleukin-6 and selected plasma proteins in healthy persons of different ages. Neurobiol Aging. 1994;15:771-772. doi:10.1016/0197-4580(94)90066-3. · DOI
  49. Ferrucci L, Corsi A, Lauretani F, et al. The origins of age-related proinflammatory state. Blood. 2005;105:2294-2299. doi:10.1182/ blood-2004-07-2599 · DOI · Paper page
  50. Anderson AE, Pratt AG, Sedhom MA, et al. IL-6-driven STAT signalling in circulating CD4 + lymphocytes is a marker for early anticitrullinated peptide antibody-negative rheumatoid arthritis. Ann Rheum Dis. 2016;75:466-473. doi:10.1136/annrheumdis-2014-205850 · DOI
  51. Isomäki P, Junttila I, Vidqvist KL, Korpela M, Silvennoinen O. The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels. Rheumatology (Oxford). 2015;54:1103-1113. doi:10.1093/rheumatology/keu430 · DOI
  52. Zhang D, Sun M, Samols D, Kushner I. STAT3 participates in transcrip- tional activation of the C-reactive protein gene by interleukin-6. J Biol Chem. 1996;271:9503-9509. doi:10.1074/jbc.271.16.9503 · DOI · Paper page
  53. Miscia S, Marchisio M, Grilli A, et al. Tumor necrosis factor alpha (TNF- alpha) activates Jak1/Stat3-Stat5B signaling through TNFR-1 in human B cells. Cell Growth Differ. 2002;13:13-18.
  54. Grech AP, Gardam S, Chan T, et al. Tumor necrosis factor receptor 2 (TNFR2) signaling is negatively regulated by a novel, carboxyl- terminal TNFR-associated factor 2 (TRAF2)-binding site. J Biol Chem. 2005;280:31572-31581. doi:10.1074/jbc. · DOI

Cited by

Sorted by citations

Authors
Piber, D., Olmstead, R., Cho, J. H.-J., Witarama, T., Perez, C., Dietz, N., Seeman, T. E., Breen, E. C., Cole, S. W., & Irwin, M. R.
Affiliations
  • University of California, Los Angeles (US)
  • Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles
Corresponding author
Irwin, Michael R
ORCID
Venue
The Journals of Gerontology: Series A
Publisher
Oxford University Press (OUP)
Published
2019-05-20
Volume
74
Issue
11
Pages
1716-1724
ISSN
  • 1079-5006 (ISSN-L)
  • 1758-535X
DOI
10.1093/gerona/glz130
PMC
PMC6777092
OpenAlex
W2945803920
Cited by
62
References
7
Citations by year
2026: 5 · 2025: 5 · 2024: 6 · 2023: 11 · 2022: 11 · 2021: 11 · 2020: 11 · 2019: 2
FWCI
3.18
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • The Journals of Gerontology Series A (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Max Kade Foundation
  • National Institutes of Health (R01AG034588)
  • UCLA Cousins Center for Psychoneuroimmunology
  • Semel Institute for Neurosciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
inflammaging, systemic inflammation, aging, older adults, interleukin-6, C-reactive protein, soluble tumor necrosis factor receptor II, TLR4, nuclear factor-kappaB, STAT activation, STAT1, STAT3, STAT5, inflammatory cytokines, community-dwelling older adults
MeSH terms
Age Factors, Aged, Aged, 80 and over, Aging, C-Reactive Protein, Cross-Sectional Studies, Female, Gene Expression Regulation, Humans, Inflammation, Male, Middle Aged, Tumor Necrosis Factor-alpha, Signal Transduction, Multivariate Analysis, Linear Models, Cytokines, Risk Assessment, Inflammation Mediators, Tumor Suppressor Proteins, STAT1 Transcription Factor, STAT3 Transcription Factor, STAT5 Transcription Factor, Independent Living

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review