Abstract
Chronic low-grade inflammation has long been considered an important part of the aging process (“inflamm-aging”). However, measurement of this process is highly variable across studies, often relying on a single marker such as C-reactive protein or interleukin-6, despite evidence for greater complexity. Several studies have now tackled multivariate approaches to integrating the signals of multiple inflammation-related cytokines in order to measure the process of inflamm-aging. On the surface, the results appear discordant, even when using the same data set. Here we review and compare these studies. We show that apparent discrepancies can easily be explained by minor methodological differences across studies. There is a single, coherent interpretation of inflamm-aging as a simultaneous up-regulation of both pro- and anti-inflammatory cytokines. This interpretation is robustly detectable with different methods and data sets. Single markers do not provide a reliable signal, but small numbers of markers can be easily integrated to provide a much more reliable metric. We recommend a minimum of 3–4 markers, including one of the soluble TNF receptors, IL-6, and some choice within TNF-α, IL-1RA, IL-18, and CRP. More broadly, these findings confirm the need for multivariate and complex systems approaches to understand underlying physiological processes.
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References
Bandeen-Roche K, Walston JD, Huang Y, Semba RD, Ferrucci L (2009) Measuring systemic inflammatory regulation in older adults: evidence and utility. Rejuvenation Res 12(6):403–410
Cannon WB (1932) The wisdom of the body. W.W. Norton, New York
Cauley JA, Danielson ME, Boudreau RM, Forrest KYZ, Zmuda JM, Pahor M, Tylavsky FA, Cummings SR, Harris TB, Newman AB (2007) Inflammatory markers and incident fracture risk in older men and women: the Health Aging and Body Composition Study. J Bone Miner Res 22(7):1088–1095
Cevenini E, Monti D, Franceschi C (2013) Inflamm-ageing. Curr Opin Clin Nutr Metab Care 16(1):14–20
Deleidi M, Jäggle M, Rubino G (2015) Immune aging, dysmetabolism, and inflammation in neurological diseases. Front Neurosci 9:172
Esposito K, Marfella R, Ciotola M et al (2004) Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 292(12):1440–1446
Ferrucci L et al (2000) Subsystems contributing to the decline in ability to walk: bridging the gap between epidemiology and geriatric practice in the InCHIANTI study. J Am Geriatr Soc 48(12):1618–1625
Ferrucci L (2009) The Baltimore Longitudinal Study on Aging: a 50 year long journey and plans for the future. G Gerontol 57:3–8
Finch CE (2007) The biology of human longevity: inflammation, nutrition, and aging in the evolution of life. Academic, San Diego
Franceschi C, Bonafé M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging: an evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908(1): 244–254
Fried LP, Borhani NO, Enright P, Furberg CD, Gardin JM, Kronmal RA, Kuller LH et al (1991) The cardiovascular health study: design and rationale. Ann Epidemiol 1(3):263–276
Goldberger AL, Amaral LAN, Hausdorff JM, Ivanov PC, Peng C-K, Stanley HE (2002) Fractal dynamics in physiology: alterations with disease and aging. Proc Natl Acad Sci 99(suppl 1):2466–2472
Harman HH (1960) Modern factor analysis. University of Chicago
Hsu F-C, Kritchevsky SB, Liu Y, Kanaya A, Newman AB, Perry SE, Visser M, Pahor M, Harris TB, Nicklas BJ (2009) Association between inflammatory components and physical function in the health, aging, and body composition study: a principal component analysis approach. J Gerontol Ser A Biol Med Sci 64(5):581–589
Hubbard RE, O’Mahony MS, Savva GM, Calver BL, Woodhouse KW (2009) Inflammation and frailty measures in older people. J Cell Mol Med 13(9b):3103–3109
Jolliffe IT (2002) Principal components analysis. Springer, New York
Kitano H (2002) Looking beyond the details: a rise in system-oriented approaches in genetics and molecular biology. Curr Genet 41(1):1–10
Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121(6):2111–2117
Martin LB, Cohen AA (2014) Physiological regulatory networks: the orchestra of life? Integr Organ Biol:137–152
Morrisette-Thomas V, Cohen AA, Fülöp T, Riesco É, Legault V, Li Q, Milot E, Dusseault-Bélanger F, Ferrucci L (2014) Inflamm-aging does not simply reflect increases in pro-inflammatory markers. Mech Ageing Dev 139(0):49–57
Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, Cesari M, Nourhashemi F (2013) Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc 14(12):877–882
Muthén B (2004) Latent variable analysis. In: The Sage handbook of quantitative methodology for the social sciences. pp 345–368
Ridker PM (2003) Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 107(3):363–369
Riesco E, Choquette S, Audet M, Lebon J, Tessier D, Dionne IJ (2012) Effect of exercise training combined with phytoestrogens on adipokines and C-reactive protein in postmenopausal women: a randomized trial. Metab Clin Exp 61(2):273–280
Rives AW, Galitski T (2003) Modular organization of cellular networks. Proc Natl Acad Sci 100(3):1128–1133
Thomas R, Thieffry D, Kaufman M (1995) Dynamical behaviour of biological regulatory networks – I. Biological role of feedback loops and practical use of the concept of the loop-characteristic state. Bull Math Biol 57(2):247–276
van der Vaart H, Postma DS, Timens W, Ten Hacken NHT (2004) Acute effects of cigarette smoke on inflammation and oxidative stress: a review. Thorax 59(8):713–721
Varadhan R, Yao W, Matteini A, Beamer BA, Xue Q-l, Yang H, Manwani B, Reiner A, Jenny N, Parekh N (2014) Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults. J Gerontol Ser A Biol Med Sci 69(2): 165–173
Vasunilashorn S, Crimmins EM, Kim JK, Winking J, Gurven M, Kaplan H, Finch CE (2010) Blood lipids, infection, and inflammatory markers in the Tsimane of Bolivia. Am J Hum Biol 22(6):731–740
Acknowledgments
Alan A. Cohen is a member of the FRQ-S-supported Centre de recherche sur le vieillissement and Centre de recherche du CHUS. This research was supported by Canadian Institutes of Health Research grant #s 110789, 120305, 119485, 106634, and 106701 and by NSERC Discovery Grant # 402079-2011, as well as by grants from the Université de Sherbrooke and the Centre de recherche sur le vieillissement to TF.
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Cohen, A.A., Bandeen-Roche, K., Morissette-Thomas, V., Fülöp, T. (2018). A Robust Characterization of Inflamm-Aging and Other Immune Processes Through Multivariate Analysis of Cytokines from Longitudinal Studies. In: Fulop, T., Franceschi, C., Hirokawa, K., Pawelec, G. (eds) Handbook of Immunosenescence. Springer, Cham. https://doi.org/10.1007/978-3-319-64597-1_120-1
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DOI: https://doi.org/10.1007/978-3-319-64597-1_120-1
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