Top

Published in:

Open Access 01-12-2022 | Cytokines | Research

Impaired JAK-STAT pathway signaling in leukocytes of the frail elderly

Authors: Leonard Daniël Samson, Peter Engelfriet, W. M. Monique Verschuren, H. Susan J. Picavet, José A. Ferreira, Mary-lène de Zeeuw-Brouwer, Anne-Marie Buisman, A. Mieke H. Boots

Published in: Immunity & Ageing | Issue 1/2022

Abstract

Background

Elderly often show reduced immune functioning and can develop chronic low-grade inflammation. Why some elderly are more prone to become frail is unknown. We investigated whether frailty is associated with altered cytokine signaling through the JAK-STAT pathway in leukocytes of 34 individuals aged 65–74 years. In addition, we investigated how this relation is affected by chronic low-grade inflammation during the previous 20 years. Cytokine signaling was quantified by measuring intracellular STAT1, STAT3, and STAT5 phosphorylation in monocytes, B cells, CD4⁺ T cells and CD8⁺ T cells upon stimulation with IL-2, IL-6, IL-10, IFNα and IFNγ, using phospho-flow cytometry. Presence of chronic low-grade inflammation was investigated by evaluating 18 different plasma inflammatory markers that had been measured repeatedly in the same individuals over the previous 20 years. Frailty was assessed as a score on a frailty index.

Results

We found that lower cytokine-induced pSTAT responsiveness in the various cell subsets was seen with higher frailty scores in both men and women, indicative of dysfunctional pSTAT responses in frailer individuals. Associations differed between men and women, with frailer women showing lower pSTAT1 responses in monocytes and frailer men showing lower pSTAT5 responses in CD4⁺ and CD8⁺ T cells. Notably, lower IL-10-induced pSTAT3 responses in men were related to both higher frailty scores and higher CRP levels over the past 20 years. This might indicate poor resolution of low-grade inflammation due to defective regulatory pSTAT signaling in older men.

Conclusions

Our results emphasize the importance of preserved JAK-STAT pathway signaling in healthy aging and reveal cellular pSTAT levels as a candidate biomarker of frailty.

Available only for authorised users

Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, et al. Geroscience: linking aging to chronic disease. Cell. 2014;159(4):709–13.PubMedPubMedCentralCrossRef

Glynn JR, Moss PAH. Systematic analysis of infectious disease outcomes by age shows lowest severity in school-age children. Sci Data. 2020;7(1):329.PubMedPubMedCentralCrossRef

Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine. 2006;24:1159.PubMedCrossRef

Gustafson CE, Kim C, Weyand CM, Goronzy JJ. Influence of immune aging on vaccine responses. J Allergy Clin Immunol. 2020;145(5):1309–21.PubMedPubMedCentralCrossRef

Aiello A, Farzaneh F, Candore G, Caruso C, Davinelli S, Gambino CM, et al. Immunosenescence and its hallmarks: how to oppose aging strategically? A review of potential options for therapeutic intervention. Front Immunol. 2019;10:2247.PubMedPubMedCentralCrossRef

Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Inflamm-aging: an evolutionary perspective on Immunosenescence. Ann N Y Acad Sci. 2006;908(1):244–54.CrossRef

Fulop T, Witkowski JM, Olivieri F, Larbi A. The integration of inflammaging in age-related diseases. Semin Immunol. 2018;40:17–35.PubMedCrossRef

Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25(12):1822–32.PubMedPubMedCentralCrossRef

Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S. Inflammaging and ‘Garb-aging’. Trends Endocrinol Metab. 2017;28(3):199–212.PubMedCrossRef

10.

van Deursen JM. The role of senescent cells in ageing. Nature. 2014;509(7501):439–46.PubMedPubMedCentralCrossRef

11.

Villarino AV, Kanno Y, O’Shea JJ. Mechanisms and consequences of Jak–STAT signaling in the immune system. Nat Immunol. 2017;18(4):374–84.PubMedCrossRef

12.

O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311–28.PubMedPubMedCentralCrossRef

13.

Dupuis S, Jouanguy E, Al-Hajjar S, Fieschi C, Al-Mohsen IZ, Al-Jumaah S, et al. Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency. Nat Genet. 2003;33(3):388–91.PubMedCrossRef

14.

Sancho-Shimizu V, Perez de Diego R, Jouanguy E, Zhang S-Y, Casanova J-L. Inborn errors of anti-viral interferon immunity in humans. Curr Opin Virol. 2011;1(6):487–96.PubMedPubMedCentralCrossRef

15.

Sandborn WJ, Su C, Sands BE, D’Haens GR, Vermeire S, Schreiber S, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723–36.PubMedCrossRef

16.

van der Heijde D, Strand V, Tanaka Y, Keystone E, Kremer J, Zerbini CAF, et al. Tofacitinib in combination with methotrexate in patients with rheumatoid arthritis: clinical efficacy, radiographic, and safety outcomes from a twenty-four–month, phase III study. Arthritis Rheum. 2019;71(6):878–91.CrossRef

17.

Shen-Orr SS, Furman D, Kidd BA, Hadad F, Lovelace P, Huang YW, et al. Defective signaling in the JAK-STAT pathway tracks with chronic inflammation and cardiovascular risk in aging humans. Cell Syst. 2016;3(4):374–384 e4.PubMedPubMedCentralCrossRef

18.

Piber D, Olmstead R, Cho JH-J, Witarama T, Perez C, Dietz N, et al. Inflammaging: age and systemic, cellular, and nuclear inflammatory biology in older adults. Le Couteur D, editor. J Gerontol Ser A. 2019;74(11):1716–24.CrossRef

19.

Febvre-James M, Lecureur V, Fardel O. Potent repression of C-reactive protein (CRP) expression by the JAK1/2 inhibitor ruxolitinib in inflammatory human hepatocytes. Inflamm Res. 2020;69(1):51–62.PubMedCrossRef

20.

Xu M, Tchkonia T, Ding H, Ogrodnik M, Lubbers ER, Pirtskhalava T, et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc Natl Acad Sci U S A. 2015;112(46):E6301–10.PubMedPubMedCentralCrossRef

21.

Bailey KL, Smith LM, Heires AJ, Katafiasz DM, Romberger DJ, LeVan TD. Aging leads to dysfunctional innate immune responses to TLR2 and TLR4 agonists. Aging Clin Exp Res. 2019;31(9):1185–93.PubMedCrossRef

22.

van den Biggelaar AHJ, Huizinga TWJ, de Craen AJM, Gussekloo J, Heijmans BT, Frölich M, et al. Impaired innate immunity predicts frailty in old age. The Leiden 85-plus study. Exp Gerontol. 2004;39(9):1407–14.PubMedCrossRef

23.

Wang Q, Westra J, van der Geest KSM, Moser J, Bijzet J, Kuiper T, et al. Reduced levels of cytosolic DNA sensor AIM2 are associated with impaired cytokine responses in healthy elderly. Exp Gerontol. 2016;78:39–46.PubMedCrossRef

24.

Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits as a proxy measure of aging. TheScientificWorldJournal. 2001;1:323–36.PubMedPubMedCentralCrossRef

25.

Searle SD, Mitnitski A, Gahbauer EA, Gill TM, Rockwood K. A standard procedure for creating a frailty index. BMC Geriatr. 2008;8:24.PubMedPubMedCentralCrossRef

26.

Picavet HSJ, Blokstra A, Spijkerman AMW, Verschuren WMM. Cohort profile update: the Doetinchem cohort study 1987-2017: lifestyle, health and chronic diseases in a life course and ageing perspective. Int J Epidemiol. 2017;46(6):1751–1751g.PubMedPubMedCentralCrossRef

27.

Verschuren WM, Blokstra A, Picavet HS, Smit HA. Cohort profile: the Doetinchem cohort study. Int J Epidemiol. 2008;37(6):1236–41.PubMedCrossRef

28.

Van der Sluis RM, Zerbato JM, Rhodes JW, Pascoe RD, Solomon A, Kumar NA, et al. Diverse effects of interferon alpha on the establishment and reversal of HIV latency. Douek DC, editor. PLoS Pathog. 2020;16(2):e1008151.PubMedPubMedCentralCrossRef

29.

Tsai WL, Vian L, Giudice V, Kieltyka J, Liu C, Fonseca V, et al. High throughput pSTAT signaling profiling by fluorescent cell barcoding and computational analysis. J Immunol Methods. 2020;477:112667.PubMedCrossRef

30.

Twohig JP, Cardus Figueras A, Andrews R, Wiede F, Cossins BC, Derrac Soria A, et al. Activation of naïve CD4+ T cells re-tunes STAT1 signaling to deliver unique cytokine responses in memory CD4+ T cells. Nat Immunol. 2019;20(4):458–70.PubMedPubMedCentralCrossRef

31.

Samson LD, Boots AMH, Ferreira JA, Picavet HSJ, de Rond LGH, de Zeeuw-Brouwer M, et al. In-depth immune cellular profiling reveals sex-specific associations with frailty. Immun Ageing. 2020;17(1):20.PubMedPubMedCentralCrossRef

32.

Marcos-Pérez D, Sánchez-Flores M, Maseda A, Lorenzo-López L, Millán-Calenti JC, Gostner JM, et al. Frailty in older adults is associated with plasma concentrations of inflammatory mediators but not with lymphocyte subpopulations. Front Immunol. 2018;9:1056.PubMedPubMedCentralCrossRef

33.

Samson LD, Boots AMH, Verschuren WMM, Picavet HSJ, Engelfriet P, Buisman A-M. Frailty is associated with elevated CRP trajectories and higher numbers of neutrophils and monocytes. Exp Gerontol. 2019;125:110674.PubMedCrossRef

34.

Walker KA, Walston J, Gottesman RF, Kucharska-Newton A, Palta P, Windham BG. Midlife systemic inflammation is associated with frailty in later life: the ARIC study. J Gerontol A Biol Sci Med Sci. 2018;34(3):343–349.

35.

Han H, Ma Q, Li C, Liu R, Zhao L, Wang W, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect. 2020;9(1):1123–30.PubMedPubMedCentralCrossRef

36.

Lu L, Zhang H, Dauphars DJ, He Y-W. A potential role of interleukin 10 in COVID-19 pathogenesis. Trends Immunol. 2020; Available from: http://www.sciencedirect.com/science/article/pii/S1471490620302568. [cited 2020 Dec 22].

37.

Takahashi T, Ellingson MK, Wong P, Israelow B, Lucas C, Klein J, et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature. 2020;588(7837):315–20.PubMedPubMedCentralCrossRef

38.

Luo W, Li Y-X, Jiang L-J, Chen Q, Wang T, Ye D-W. Targeting JAK-STAT signaling to control cytokine release syndrome in COVID-19. Trends Pharmacol Sci. 2020;41(8):531–43.PubMedPubMedCentralCrossRef

39.

Hojyo S, Uchida M, Tanaka K, Hasebe R, Tanaka Y, Murakami M, et al. How COVID-19 induces cytokine storm with high mortality. Inflamm Regen. 2020;40(1):37.PubMedPubMedCentralCrossRef

40.

Gozzetti A, Capochiani E, Bocchia M. The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19. Leukemia. 2020;34(10):2815–6.PubMedCrossRef

41.

La Rosée F, Bremer HC, Gehrke I, Kehr A, Hochhaus A, Birndt S, et al. The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation. Leukemia. 2020;34(7):1805–15.PubMedPubMedCentralCrossRef

42.

Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V, et al. Baricitinib plus Remdesivir for hospitalized adults with Covid-19. N Engl J Med. 2020; Available from: https://www.nejm.org/doi/10.1056/NEJMoa2031994. [cited 2020 Dec 22].

43.

Novartis. Novartis provides update on RUXCOVID study of ruxolitinib for hospitalized patients with COVID-19. Novartis. 2020; Available from: https://www.novartis.com/news/media-releases/novartis-provides-update-ruxcovid-study-ruxolitinib-hospitalized-patients-covid-19. [cited 2020 Dec 23].

44.

Dodington DW, Desai HR, Woo M. JAK/STAT – emerging players in metabolism. Trends Endocrinol Metab. 2018;29(1):55–65.PubMedCrossRef

45.

Sehgal PB, Yang Y-M, Yuan H, Miller EJ. STAT5a/b contribute to sex bias in vascular disease: a neuroendocrine perspective. JAK-STAT. 2015;4(3):1–20.PubMedPubMedCentralCrossRef

46.

Liao Z, Lutz J, Nevalainen MT. Transcription factor Stat5a/b as a therapeutic target protein for prostate cancer. Int J Biochem Cell Biol. 2010;42(2):186–92.PubMedCrossRef

47.

Leehy KA, Truong TH, Mauro LJ, Lange CA. Progesterone receptors (PR) mediate STAT actions: PR and prolactin receptor signaling crosstalk in breast cancer models. J Steroid Biochem Mol Biol. 2018;176:88–93.PubMedCrossRef

48.

Young NA, Valiente GR, Hampton JM, Wu L-C, Burd CJ, Willis WL, et al. Estrogen-regulated STAT1 activation promotes TLR8 expression to facilitate signaling via microRNA-21 in systemic lupus erythematosus. Clin Immunol. 2017;176:12–22.PubMedCrossRef

49.

Duong L, Radley H, Lee B, Dye D, Pixley F, Grounds M, et al. Macrophage function in the elderly and impact on injury repair and cancer. Immun Ageing. 2021;18(1):4.PubMedPubMedCentralCrossRef

50.

Samson LD, Buisman A-M, Ferreira JA, Picavet HSJ, Verschuren WMM, Boots AMH, et al. Relation of inflammatory marker trajectories with frailty and aging in a 20-year longitudinal study. bioRxiv. 2021:2021.02.10.430670. https://doi.org/10.1101/2021.02.10.430670.

51.

Collerton J, Martin-Ruiz C, Davies K, Hilkens CM, Isaacs J, Kolenda C, et al. Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: cross-sectional findings from the Newcastle 85+ study. Mech Ageing Dev. 2012;133(6):456–66.PubMedCrossRef

52.

Schoufour JD, Erler NS, Jaspers L, Kiefte-de Jong JC, Voortman T, Ziere G, et al. Design of a frailty index among community living middle-aged and older people: the Rotterdam study. Maturitas. 2017;97:14–20.PubMedCrossRef

53.

Krutzik PO, Nolan GP. Fluorescent cell barcoding in flow cytometry allows high-throughput drug screening and signaling profiling. Nat Methods. 2006;3(5):361–8.PubMedCrossRef

54.

Hulsegge G, Herber-Gast GC, Spijkerman AM, Susan H, Picavet J, van der Schouw YT, et al. Obesity and age-related changes in markers of oxidative stress and inflammation across four generations. Obesity (Silver Spring). 2016;24(6):1389–96.CrossRef

55.

Hothorn T, Winell H, Hornik K, van de Wiel MA, Zeileis A. Coin: conditional inference procedures in a permutation test framework. 2019. Available from: https://CRAN.R-project.org/package=coin.

56.

Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol. 1995;57(1):289–300.

57.

R Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2019. Available from: https://www.R-project.org/

58.

Wickham H, François R, Henry L, Müller K. dplyr: a grammar of data manipulation. 2020. Available from: https://CRAN.R-project.org/package=dplyr.

59.

Wickham H, Henry L. tidyr: tidy messy data. 2020. Available from: https://CRAN.R-project.org/package=tidyr.

60.

Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics. 2016;32(18):2847–9.PubMedCrossRef

61.

Wickham H, Chang W, Henry L, Pedersen TL, Takahashi K, Wilke C, et al. ggplot2: create elegant data visualisations using the grammar of graphics. 2019. Available from: https://CRAN.R-project.org/package=ggplot2.

62.

Wilke CO. cowplot: Streamlined plot theme and plot annotations for “ggplot2”. 2019. Available from: https://CRAN.R-project.org/package=cowplot.

63.

Xie Y. knitr: a general-purpose package for dynamic report generation in r. 2020. Available from: https://yihui.org/knitr/.

64.

Zhu H. kableExtra: construct complex table with “kable” and pipe syntax. 2020. Available from: https://CRAN.R-project.org/package=kableExtra.

Title: Impaired JAK-STAT pathway signaling in leukocytes of the frail elderly
Authors: Leonard Daniël Samson
Peter Engelfriet
W. M. Monique Verschuren
H. Susan J. Picavet
José A. Ferreira
Mary-lène de Zeeuw-Brouwer
Anne-Marie Buisman
A. Mieke H. Boots
Publication date: 01-12-2022
Publisher: BioMed Central
Keyword: Cytokines
Published in: Immunity & Ageing / Issue 1/2022
Electronic ISSN: 1742-4933
DOI: https://doi.org/10.1186/s12979-021-00261-w

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2022

Composition of the infiltrating immune cells in the brain of healthy individuals: effect of aging

Inflammation and cell-to-cell communication, two related aspects in frailty

Correction: Salutary effects of moderate but not high intensity aerobic exercise training on the frequency of peripheral T-cells associated with immunosenescence in older women at high risk of breast cancer: a randomized controlled trial

Correction: Neo-epitopes emerging in the degenerative hippocampal granules of aged mice can be recognized by natural IgM auto-antibodies

NKT-like (CD3 + CD56+) cells differ from T cells in expression level of cellular protective proteins and sensitivity to stimulation in the process of ageing

The diseased kidney: aging and senescent immunology

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials