Frailty: a controversial role of inflammaging
AbstractFrailty is one of the main geriatric syndromes, closely associated with human aging. The pathogenesis of frailty has not been sufficiently studied, but the role of inflammaging as a key mechanism in the development of this syndrome is of considerable interest. The review considers the contribution of pro- and anti-inflammatory cytokines associated with the innate immune system, a number of other inflammatory factors to the development of frailty and its main phenotypic manifestations. The controversial role of inflammatory aging in the pathogenesis of frailty is discussed. On the one hand, inflammaging is one of the key features of frailty, but it is not clear whether it is a pathogenetic factor or a consequence of it`s development. On the other hand, in frailty, innate immunity is impaired, expressed in a decrease in the ability to produce pro- and anti-inflammatory cytokines under the influence of TLR ligands, which is a significant predictor of mortality. The need for further search for inflammatory markers of the transition from physiological aging to age-related diseases and syndromes, in particular, to frailty, is emphasized.
Keywords:frailty; inflammaging; innate immunity; proinflammatory cytokines; polymorphic variants of genes; longevity; age-associated diseases
For citation: Artemyeva O.V., Grechenko V.V., Gromova T.V., Gankovskaya L.V. Frailty: a controversial role of inflammaging. Immunologiya. 2022; 43 (6): 746–56. DOI: https://doi.org/10.33029/0206-4952-2022-43-746-756 (in Russian)
Funding. The study had no sponsor support.
Conflict of interests. Authors declare no conflict of interests.
Authors’ contribution. General concept of the review – Artemyeva O.V., Gankovskaya L.V.; search and analysis of literature, writing the text – Artemyeva O.V., Gankovskaya L.V., Grechenko V.V., Gromova T.V.; editing – Artemyeva O.V.
References
1. Bruunsgaard H., Andersen-Ranberg K., Hjelmborg J.B, Pedersen B.K., Jeune B. Elevated levels of tumor necrosis factor alpha and mortality in centenarians. Am. J. Med. 2003; 115: 278–83. DOI: https://doi.org/10.1016/s0002-9343(03)00329-2
2. Puzianowska-Kuznicka M., Owczarz M., Wieczorowska-Tobis K., Nadrowski P., Chudek J., Slusarczyk P., Skalska A., Jonas M., Franek E., Mossakowska M. Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study. Immun. Ageing. 2016; 13: 21. DOI: https://doi.org/10.1186/s12979-016-0076-x
3. Rea I.M., Gibson D.S., McGilligan V., McNerlan S.E., Alexander H.D., Ross O.A. Age and age-related diseases: role of inflammation triggers and cytokines. Front. Immunol. 2018; 9: 586. DOI: https://doi.org/10.3389/fimmu.2018.00586
4. Minciullo P.L., Catalano A., Mandraffino G., Casciaro M., Crucitti A., Maltese G., Morabito N., Lasco A., Gangemi S., Basile G. Inflammaging and anti-inflammaging: the role of cytokines in extreme longevity. Arch. Immunol. Ther. Exp. 2016; 64 (2): 111–26. DOI: https://doi.org/10.1007/s00005-015-0377-3
5. Kinzenbaw D.A., Chu Y., Peña Silva R.A., Didion S.P., Faraci F.M. Interleukin-10 protects against aging-induced endothelial dysfunction. Physiol. Rep. 2013; 1 (6): e00149. DOI: https://doi.org/10.1002/phy2.149
6. Krieglstein K., Miyazono K., Ten Dijke P., Unsicker K. TGF-beta in aging and disease. Cell Tissue Res. 2012; 347: 5–9. DOI: https://doi.org/10.1007/s00441-011-1278-1273
7. Chen X., Mao G., Leng S.X. Frailty syndrome: an overview. Clin. Interv. Aging. 2014; 9: 433–41. DOI: https://doi.org/10.2147/CIA.S45300
8. Newman A.B., Gottdiener J.S., Mcburnie M.A., Hirsch C.H., Kop W.J., Tracy R., Walston J.D., Fried L.P. Associations of subclinical cardiovascular disease with frailty. J. Gerontol. A Biol. Sci. Med. Sci. 2001; 56 (3): M158–66. DOI: https://doi.org/10.1093/gerona/56.3.m158
9. 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. 2009; 13 (9В): 3103–9. DOI: https://doi.org/10.1111/j.1582-4934.2009.00733.x
10. Zhu Y., Liu Z., Wang Y., Wang Z., Shi J., Xie X., Jin L. Chu X., Wang X. C-reactive protein, frailty and overnight hospital admission in elderly individuals: a population-based study. Arch. Gerontol. Geriatr. 2016; 64: 1–5. DOI: https://doi.org/10.1016/j.archger.2015.08.009
11. Collerton J., Martin-Ruiz C., Davies K., Hilkens C.M., Isaacs J., Kolenda C., Parker C., Dunn M., Catt M., Jagger C., von Zglinicki T., Kirkwood T.B.L. 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. DOI: https://doi.org/10.1016/j.mad.2012.05.005
12. Soysal P., Stubbs B., Lucato P., Luchini C., Solmi M., Peluso R., Sergi G., Isik A.T., Manzato E., Maggi S., Maggio M., Prina A.M., Cosco T.D., Wu Y.-T., Veronese N. Inflammation and frailty in the elderly: a systematic review and meta-analysis. Ageing Res. Rev. 2016; 31: 1–8. DOI: https://doi.org/10.1016/j.arr.2016.08.006
13. Ma L., Sha G., Zhang Y., Li Y. Elevated serum IL-6 and adiponectin levels are associated with frailty and physical function in Chinese older adults. Clin. Interv. Aging. 2018; 13: 2013–20. DOI: https://doi.org/10.2147/CIA.S180934
14. Rønning B., Wyller T.B., Seljeflot I., Jordhoy M.S., Skovlund E., Nesbakken A., Kristjansson S.R. Frailty measures, inflammatory biomarkers and post-operative complications in older surgical patients. Age Ageing. 2010; 39 (6): 758–61. DOI: https://doi.org/10.1093/ageing/afq123
15. Leng S.X., Yang H., Walston J.D. Decreased cell proliferation and altered cytokine production in frail older adults. Aging Clin. Exp. Res. 2004; 16 (3): 249–52. DOI: https://doi.org/10.1007/BF03327392
16. Leng S.X., Xue Q.-L., Tian J., Walston J.D., Fried L.P. Inflammation and frailty in older women. J. Am. Geriatr. Soc. 2007; 55 (6): 864–71. DOI: https://doi.org/10.1111/j.1532-5415.2007.01186.x
17. Leng S.X., Xue Q.-L., Tian J., Huang Y., Yeh S.-H., Fried L.P. Associations of neutrophil and monocyte counts with frailty in community-dwelling disabled older women: results from the Women’s Health and Aging Studies I. Exp. Gerontol. 2009; 44 (8): 511–6. DOI: https://doi.org/10.1016/j.exger.2009.05.005
18. Marcos-Pérez D., Sánchez-Flores M., Maseda A., Lorenzo-López L., Millán-Calenti J.C., Gostner J.M., Fuchs D., Pásaro E., Laffon B., Valdiglesias V. Frailty in older adults is associated with plasma concentrations of inflammatory mediators but not with lymphocyte subpopulations. Front. Immunol. 2018; 9: 1056. DOI: https://doi.org/10.3389/fimmu.2018.01056
19. Walston J., Hadley E.C., Ferrucci L., Guralnik J.M., Newman A.B., Studenski S.A., Ershler W.B., Harris T., Fried L.P. Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc. 2006; 54 (6): 991–1001. DOI: https://doi.org/10.1111/j.1532-5415.2006.00745.x
20. Gale C.R., Baylis D., Cooper C., Sayer A.A. Inflammatory markers and incident frailty in men and women: the English Longitudinal Study of Ageing. Age (Dordr.). 2013; 35 (6): 2493–501. DOI: https://doi.org/10.1007/s11357-013-9528-9
21. Puts M.T, Visser M., Twisk J.W., Deeg D.J., Lips P. Endocrine and inflammatory markers as predictors of frailty. Clin. Endocrinol. (Oxf.). 2005; 63 (4): 403–11. DOI: https://doi.org/10.1111/j.1365-2265.2005.02355.x
22. Qu T., Yang H., Walston J.D., Fedarko N.S., Leng S.X. Upregulated monocytic expression of CXC chemokine ligand 10 (CXCL-10) and its relationship with serum interleukin-6 levels in the syndrome of frailty. Cytokine. 2009; 46 (3): 319–24. DOI: https://doi.org/10.1016/j.cyto.2009.02.015
23. Liu C.K., Lyass A., Larson M.G., Massaro J.M., Wang N., D’Agostino Sr R.B., Benjamin E.J., Murabito J.M. Biomarkers of oxidative stress are associated with frailty: The Framingham Offspring Study. Age (Dordr.). 2016; 38 (1): 1. DOI: https://doi.org/10.1007/s11357-015-9864-z
24. Baylis D., Bartlett D.B., Syddall H.E., Ntani G., Gale C.R., Cooper C., Lord J.M., Sayer A.A. Immune-endocrine biomarkers as predictors of frailty and mortality: a 10-year longitudinal study in community-dwelling older people. Age (Dordr.). 2013; 35 (3): 963–71. DOI: https://doi.org/10.1007/s11357-012-9396-8
25. Lai H.-Y., Chang H., Lee Y.L., Hwang S.-J. Association between inflammatory markers and frailty in institutionalized older men. Maturitas. 2014; 79 (3): 329–33. DOI: https://doi.org/10.1016/j.maturitas.2014.07.014
26. Reiner A.P., Aragaki A.K., Gray S.L., Wactawski-Wende J., Cauley J.A, Cochrane B.B., Kooperberg C.L., Woods N.F, LaCroix A.Z. Inflammation and thrombosis biomarkers and incident frailty in postmenopausal women. Am. J. Med. 2009; 122 (10): 947–54. DOI: https://doi.org/10.1016/j.amjmed.2009.04.016
27. Vetrano D.L., Palmer K., Marengoni A., Marzetti E., Lattanzio F., Roller-Wirnsberger R., Lopez Samaniego L., Rodríguez-Mañas L., Bernabei R., Onder G. Frailty and multimorbidity: a systematic review and meta-analysis. J. Gerontol. A Biol. Sci. Med. Sci. 2019; 74 (5): 659–66. DOI: https://doi.org/10.1093/gerona/gly110
28. Leng S.X., Tian X., Matteini A., Li H., Hughes J., Jain A., Walston J.D., Fedarko N.S. IL-6-independent association of elevated serum neopterin levels with prevalent frailty in community-dwelling older adults. Age Ageing. 2011; 40 (4): 475–81. DOI: https://doi.org/10.1093/ageing/afr047
29. Lealdini V., Trufelli D.C., Ferreira da Silva F.B., Costa Normando S.R., Camargo E.W., de Matos L.L., Affonso Fonseca F.L., Santi P.X., Del Giglio A. Applicability of modified Glasgow Prognostic Score in the assessment of elderly patients with cancer: a pilot study. J. Geriatr. Oncol. 2015; 6 (6): 479–83. DOI: https://doi.org/10.1016/j.jgo.2015.09.001
30. Aguirre L.E., Jan I.Z., Fowler K., Waters D.L., Villareal D.T., Armamento-Villareal R. Testosterone and adipokines are determinants of physical performance, strength, and aerobic fitness in frail, obese, older adults. Int. J. Endocrinol. 2014; 2014: 507395. DOI: https://doi.org/10.1155/2014/507395
31. Boxer R.S., Dauser D.A., Walsh S.J., Hager W.D., Kenny A.M. The association between vitamin D and inflammation with the 6-minute walk and frailty in patients with heart failure. J. Am. Geriatr. Soc. 2008; 56 (3): 454–61. DOI: https://doi.org/10.1111/j.1532-5415.2007.01601.x
32. Alemán H., Esparza J., Ramirez F.A., Astiazaran H., Payette H. Longitudinal evidence on the association between interleukin-6 and C-reactive protein with the loss of total appendicular skeletal muscle in free-living older men and women. Age Ageing. 2011; 40 (4): 469–75. DOI: https://doi.org/10.1093/ageing/afr040
33. Ferrucci L., Penninx B.W., Volpato S., Harris T.B., Bandeen-Roche K., Balfour J., Leveille S.G., Fried L.P., Guralnik J.M. Change in muscle strength explains accelerated decline of physical function in older women with high interleukin-6 serum levels. J. Am. Geriatr. Soc. 2002; 50 (12): 1947–54. DOI: https://doi.org/10.1046/j.1532-5415.2002.50605.x
34. Canon M.E., Crimmins E.M. Sex differences in the association between muscle quality, inflammatory markers, and cognitive decline. J. Nutr. Health Aging. 2011; 15 (8): 695–8. DOI: https://doi.org/10.1007/s12603-011-0340-x
35. Bourdel-Marchasson I., Laksir H., Puget E. Interpreting routine biochemistry in those aged over 65 years: a time for change. Maturitas. 2010; 66 (1): 39–45. DOI: https://doi.org/10.1016/j.maturitas.2010.02.004
36. Nilsson J., Jovinge S., Niemann A., Reneland R., Lithell H. Relation between plasma tumour necrosis factor-α and insulin sensitivity in elderly men with non-insulin-dependent diabetes mellitus. Arterioscler. Thromb. Vasc. Biol. 1998; 18 (8): 1199. DOI: https://doi.org/10.1161/01.ATV.18.8.1199
37. Frayling T.M., Rafiq S., Murray A., Hurst A.J., Weedon M.N., Henley W., Bandinelli S., Corsi A.-M., Ferrucci L., Guralnik J.M., Wallace R.B., Melzer D. An interleukin-18 polymorphism is associated with reduced serum concentrations and better physical functioning in older people. J. Gerontol. A Biol. Sci. Med. Sci. 2007; 62 (1): 73–8. DOI: https://doi.org/10.1093/gerona/62.1.73
38. Giovannini S., Onder G., Liperoti R., Russo A., Carter C., Capoluongo E., Pahor M., Bernabei R., Landi F. Interleukin-6, C-reactive protein, and tumor necrosis factor-alpha as predictors of mortality in frail, community-living elderly individuals. J. Am. Geriatr. Soc. 2011; 59 (9): 1679–85. DOI: https://doi.org/10.1111/j.1532-5415.2011.03570.x
39. Van Epps P., Oswald D., Higgins P.A., Hornick T.R., Aung H., Banks R.E., Wilson B.M., Burant C., Graventstein S., Canaday D.H. Frailty has a stronger association with inflammation than age in older veterans. Immun. Ageing. 2016; 13: 27. DOI: https://doi.org/10.1186/s12979-016-0082-z
40. Walker K.A., Walston J., Gottesman R.F., Kucharska-Newton A., Palt P., Windham B.G. Midlife systemic inflammation is associated with frailty in later life: the ARIC study. J. Gerontol. A Biol. Sci. Med. Sci. 2019; 74 (3): 343–9. DOI: https://doi.org/10.1093/gerona/gly045
41. Yao X., Li H., Leng S.X. Inflammation and immune system alterations in frailty. Clin. Geriatr. Med. 2011; 27 (1): 79–87. DOI: https://doi.org/10.1016/j.cger.2010.08.002
42. Van den Biggelaar A.H., Huizinga T.W., de Craen A.J., Gussekloo J., Heijmans B.T., Frölich M., Westendorp R.G. Impaired innate immunity predicts frailty in old age. The Leiden 85-plus study. Exp. Gerontol. 2004; 39 (9): 1407–14. DOI: https://doi.org/10.1016/j.exger.2004.06.009
43. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 2003; 3 (2): 133–46. DOI: https://doi.org/10.1038/nri1001
44. Compte N., Zouaoui Boudjeltia K., Vanhaeverbeek M., De Bruecker S., Tassignon J., Trelcat A., Pepersack T., Goriely S. Frailty in old age is associated with decreased interleukin 12/23 production in response to toll-like receptor ligation. PLoS One. 2013; 8 (6): e65325. DOI: https://doi.org/10.1371/journal.pone.0065325
45. Thomasini R.L., Pereira D.S., Pereira F.S.M., Mateo E.C., Mota T.N., Guimarães G.G., Pereira L.S.M., Lima C.X., Teixeira M.M., Teixeira Jr A.L. Aged-associated cytomegalovirus and Epstein-Barr virus reactivation and cytomegalovirus relationship with the frailty syndrome in older women. PLoS One. 2017; 12 (7): e0180841. DOI: https://doi.org/10.1371/journal.pone.0180841
46. Noppert G.A., Aiello A.E., O’Rand A.M., Cohen H.J. Investigating pathogen burden in relation to a cumulative deficits index in a representative sample of US adults. Epidemiol. Infect. 2018; 146 (15): 1968–76. DOI: https://doi.org/10.1017/S095026881800153X
47. Aiello A.E., Haan M., Blythe L., Moore K., Gonzalez J.M., Jagust W. The influence of latent viral infection on rate of cognitive decline over 4 years. J. Am. Geriatr. Soc. 2006; 54 (7): 1046–54. DOI: https://doi.org/10.1111/j.1532-5415.2006.00796.x
48. Readhead B., Haure-Mirande J.-V., Funk C.C., Richards M.A., Shannon P., Haroutunian V., Sano M., Liang W.S., Beckmann N.D, Price N.D., Reiman E.M., Schadt E.E., Ehrlich M.E., Gandy S., Dudley J.T. Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron. 2018; 99 (1): 64–82.e7. DOI: https://doi.org/10.1016/j.neuron.2018.05.023
49. Lu Y., Tan C.T.Y., Gwee X., Yap K.B., Fulop T., Pan F., Larbi A., Ng T.P. Pathogen burden, blood biomarkers, and functional aging in community-dwelling older adults. J. Gerontol. A Biol. Sci. Med. Sci. 2021; 76 (10): 1864–73. DOI: https://doi.org/10.1093/gerona/glab057 PMID: 33640984.
50. Артемьева О.В., Ганковская Л.В. Роль полиморфных вариантов генов врожденного иммунитета при долголетии и возраст-ассоциированных заболеваниях. Иммунология. 2022; 43 (3): 333–342. DOI: https://doi.org/10.33029/0206-4952-2022-43-3-333-342
51. 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 Alzheimers disease: a meta-analysis. J. Neurol. 2012; 259 (3): 414–9. DOI: https://doi.org/10.1007/s00415-011-6164-0
52. Hurme M., Lehtimaki T., Jylha M., Karhunen P.J., Hervonen A. Interleukin-6 −174G/C polymorphism and longevity: a follow-up study. Mech. Ageing Dev. 2005; 126 (3): 417–8. DOI: https://doi.org/10.1016/j.mad.2004.10.001
53. Hou H., Wang C., Sun F., Zhao L., Dun A., Sun Z. Association of interleukin-6 gene polymorphism with coronary artery disease: an updated systematic review and cumulative meta-analysis. Inflamm. Res. 2015; 64 (9): 707–20. DOI: https://doi.org/10.1007/s00011-015-0850-9
54. Walston J., Arking D.Е., Fallin D., Li T., Beamer B., Xue Q., Ferrucci L., Fried L.P., Chakravarti A. IL-6 gene variation is not associated with increased serum levels of IL-6, muscle, weakness, or frailty in older women. Exp. Gerontol. 2005; 40 (4): 344–52. DOI: https://doi.org/10.1016/j.exger.2005.01.012
55. Zhang P., Wu X., Li G., He Q., Dai H., Ai C., Shi J. Tumor necrosis factor-alpha gene polymorphisms and susceptibility to ischemic heart disease: a systematic review and meta-analysis. Medicine (Baltimore). 2017; 96 (14): e6569. DOI: https://doi.org/10.1097/MD.0000000000006569
56. Zhao Y., Li Z., Zhang L., Zhang Y., Yang Y., Tang Y., Fu P. The TNF-alpha -308G/A polymorphism is associated with type 2 diabetes mellitus: an updated meta-analysis. Mol. Biol. Rep. 2014; 41 (1): 73–83. DOI: https://doi.org/10.1007/s11033-013-2839-1
57. Saleh A., Sultan A., Elashry M.A., Farag A., Mortada M.I., Ghannam M.A., Saed A.M., Ghoneem S. Association of TNF-α G-308 a promoter polymorphism with the course and outcome of COVID-19 patients. Immunol. Investig. 2022; 51 (3): 546–57. DOI: https://doi.org/10.1080/08820139.2020.1851709
58. Mekli K., Nazroo J.Y., Marshall A.D., Kumari M., Pendleton N. Proinflammatory genotype is associated with the frailty phenotype in the English Longitudinal Study of Ageing. Aging Clin. Exp. Res. 2016; 28 (3): 413–21. DOI: https://doi.org/10.1007/s40520-015-0419-z
59. Mekli K., Marshall A., Nazroo J., Vanhoutte B., Pendleton N. Genetic variant of Interleukin-18 gene is associated with the Frailty Index in the English Longitudinal Study of Ageing. Age Ageing 2015; 44 (6): 938–42. DOI: https://doi.org/10.1093/ageing/afv122
60. Lio D., Candore G., Crivello A., Scola L., Colonna-Romano G., Cavallone L., Hoffmann E., Caruso M., Licastro F., Caldarera C.M., Branzi A., Franceschi C., Caruso C. Opposite effects of interleukin 10 common gene polymorphisms in cardiovascular diseases and in successful ageing: genetic background of male centenarians is protective against coronary heart disease. J. Med. Genet. 2004; 41 (10): 790–4. DOI: https://doi.org/10.1136/jmg.2004.019885
61. Juárez-Cedillo T., Vargas-Alarcón G., Martínez Rodríguez N., Juárez-Cedillo E., Fragoso J.M., Escobedo-de-la-Peña J. Interleukin 10 gene polymorphisms and frailty syndrome in elderly Mexican people: Sadem study. Mol. Genet. Genomic Med. 2019; 7 (9): e918. DOI: https://doi.org/10.1002/mgg3.918