The American Journal of Medicine
Volume 122, Issue 7 , Pages 605-613 , July 2009

Inflammation, Coagulation, and the Pathway to Frailty

  • Bindu Kanapuru, MD
    • ,
  • William B. Ershler, MD

      Affiliations

    • Corresponding Author InformationRequests for reprints should be addressed to William B. Ershler, MD, National Institute on Aging, Harbor Hospital, 3001 S. Hanover St, Baltimore, MD 212225

References 

  1. Rockwood K, Mitnitski A, Song X, Steen B, Skoog I. Long-term risks of death and institutionalization of elderly people in relation to deficit accumulation at age 70. J Am Geriatr Soc. 2006;54:975–979
  2. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146–M156
  3. Boyd CM, Xue QL, Guralnik JM, Fried LP. Hospitalization and development of dependence in activities of daily living in a cohort of disabled older women: the Women's Health and Aging Study I. J Gerontol A Biol Sci Med Sci. 2005;60:888–893
  4. Boyd CM, Xue QL, Simpson CF, et al. Frailty, hospitalization, and progression of disability in a cohort of disabled older women. Am J Med. 2005;118:1225–1231
  5. Rockwood K, Howlett SE, MacKnight C, et al. Prevalence, attributes, and outcomes of fitness and frailty in community-dwelling older adults: report from the Canadian Study of Health and Aging. J Gerontol A Biol Sci Med Sci. 2004;59:1310–1317
  6. Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med. 2000;51:245–270
  7. Fries JF. Aging, natural death, and the compression of morbidity. N Engl J Med. 1980;303:130–135
  8. Vaupel JW, Carey JR, Christensen K, et al. Biodemographic trajectories of longevity. Science. 1998;280:855–860
  9. Klein BE, Klein R, Knudtson MD, Lee KE. Frailty, morbidity and survival. Arch Gerontol Geriatr. 2005;41:141–149
  10. Yancik R, Ershler W, Satariano W, et al. Report of the National Institute on Aging task force on comorbidity. J Gerontol A Biol Sci Med Sci. 2007;62:275–280
  11. Rockwood K, Andrew M, Mitnitski A. A comparison of two approaches to measuring frailty in elderly people. J Gerontol A Biol Sci Med Sci. 2007;62:738–743
  12. Fried LP, Borhani NO, Enright P, et al. The Cardiovascular Health Study: design and rationale. Ann Epidemiol. 1991;1:263–276
  13. Bandeen-Roche K, Xue Q-L, Ferrucci L, et al. Phenotype of frailty: characterization in the Women's Health and Aging Studies. J Gerontol A Biol Sci Med Sci. 2006;61:262–266
  14. Leng SX, Xue QL, Tian J, et al. Inflammation and frailty in older women. J Am Geriatr Soc. 2007;55:864–871
  15. Woods NF, LaCroix AZ, Gray SL, et al. Frailty: emergence and consequences in women aged 65 and older in the Women's Health Initiative Observational Study. J Am Geriatr Soc. 2005;53:1321–1330
  16. Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005;173:489–495
  17. Jones D, Song X, Mitnitski A, Rockwood K. Evaluation of a frailty index based on a comprehensive geriatric assessment in a population based study of elderly Canadians. Aging Clin Exp Res. 2005;17:465–471
  18. Gill TM, Gahbauer EA, Allore HG, Han L. Transitions between frailty states among community-living older persons. Arch Intern Med. 2006;166:418–423
  19. Hardy SE, Dubin JA, Holford TR, Gill TM. Transitions between states of disability and independence among older persons. Am J Epidemiol. 2005;161:575–584
  20. Puts MT, Lips P, Deeg DJ. Static and dynamic measures of frailty predicted decline in performance-based and self-reported physical functioning. J Clin Epidemiol. 2005;58:1188–1198
  21. Puts MT, Lips P, Deeg DJ. Sex differences in the risk of frailty for mortality independent of disability and chronic diseases. J Am Geriatr Soc. 2005;53:40–47
  22. Chin APMJ, de Groot LC, van Gend SV, et al. Inactivity and weight loss: effective criteria to identify frailty. J Nutr Health Aging. 2003;7:55–60
  23. Hirsch C, Anderson ML, Newman A, et al. The association of race with frailty: the cardiovascular health study. Ann Epidemiol. 2006;16:545–553
  24. Newman AB, Gottdiener JS, McBurnie MA, et al. Associations of subclinical cardiovascular disease with frailty. J Gerontol A Biol Sci Med Sci. 2001;56:M158–M166
  25. Strawbridge WJ, Shema SJ, Balfour JL, et al. Antecedents of frailty over three decades in an older cohort. J Gerontol B Psychol Sci Soc Sci. 1998;53:S9–S16
  26. Blaum CS, Xue QL, Michelon E, et al. The association between obesity and the frailty syndrome in older women: the Women's Health and Aging Studies. J Am Geriatr Soc. 2005;53:927–934
  27. Woo J, Leung J, Kwok T. BMI, body composition, and physical functioning in older adults. Obesity. 2007;15:1886–1894
  28. Zoico E, Di Francesco V, Mazzali G, et al. High baseline values of fat mass, independently of appendicular skeletal mass, predict 2-year onset of disability in elderly subjects at the high end of the functional spectrum. Aging Clin Exp Res. 2007;19:154–159
  29. Visser M, Harris TB, Langlois J, et al. Body fat and skeletal muscle mass in relation to physical disability in very old men and women of the Framingham Heart Study. J Gerontol A Biol Sci Med Sci. 1998;53:M214–M221
  30. Payette H, Roubenoff R, Jacques PF, et al. Insulin-like growth factor-1 and interleukin 6 predict sarcopenia in very old community-living men and women: the Framingham Heart Study. J Am Geriatr Soc. 2003;51:1237–1243
  31. Iannuzzi-Sucich M, Prestwood KM, Kenny AM. Prevalence of sarcopenia and predictors of skeletal muscle mass in healthy, older men and women. J Gerontol A Biol Sci Med Sci. 2002;57:M772–M777
  32. Harris TB, Kiel D, Roubenoff R, et al. Association of insulin-like growth factor-I with body composition, weight history, and past health behaviors in the very old: the Framingham Heart Study. J Am Geriatr Soc. 1997;45:133–139
  33. Mohr BA, Bhasin S, Kupelian V, et al. Testosterone, sex hormone-binding globulin, and frailty in older men. J Am Geriatr Soc. 2007;55:548–555
  34. Ble A, Cherubini A, Volpato S, et al. Lower plasma vitamin E levels are associated with the frailty syndrome: the InCHIANTI study. J Gerontol A Biol Sci Med Sci. 2006;61:278–283
  35. Michelon E, Blaum C, Semba RD, et al. Vitamin and carotenoid status in older women: associations with the frailty syndrome. J Gerontol A Biol Sci Med Sci. 2006;61:600–607
  36. Semba RD, Bartali B, Zhou J, et al. Low serum micronutrient concentrations predict frailty among older women living in the community. J Gerontol A Biol Sci Med Sci. 2006;61:594–549
  37. Tuomisto K, Jousilahti P, Sundvall J, et al. C-reactive protein, interleukin-6 and tumor necrosis factor alpha as predictors of incident coronary and cardiovascular events and total mortality (A population-based, prospective study). Thromb Haemost. 2006;95:511–518
  38. Margolis KL, Manson JE, Greenland P, et al. Leukocyte count as a predictor of cardiovascular events and mortality in postmenopausal women: the Women's Health Initiative Observational Study. Arch Intern Med. 2005;165:500–508
  39. Brown DW, Giles WH, Croft JB. White blood cell count: an independent predictor of coronary heart disease mortality among a national cohort. J Clin Epidemiol. 2001;54:316–322
  40. Cesari M, Penninx BW, Newman AB, et al. Inflammatory markers and cardiovascular disease (The Health, Aging and Body Composition [Health ABC] Study). Am J Cardiol. 2003;92:522–528
  41. Pai JK, Pischon T, Ma J, et al. Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med. 2004;351:2599–2610
  42. Leng S, Chaves P, Koenig K, Walston J. Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study. J Am Geriatr Soc. 2002;50:1268–1271
  43. Spranger J, Kroke A, Mohlig M, et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes. 2003;52:812–817
  44. Hu FB, Meigs JB, Li TY, et al. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes. 2004;53:693–700
  45. Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327–334
  46. Ferrucci L, Harris TB, Guralnik JM, et al. Serum IL-6 level and the development of disability in older persons. J Am Geriatr Soc. 1999;47:639–646
  47. Bruunsgaard H, Andersen-Ranberg K, Hjelmborg JB, et al. Elevated levels of tumor necrosis factor alpha and mortality in centenarians. Am J Med. 2003;115:278–283
  48. Puts MT, Visser M, Twisk JW, et al. Endocrine and inflammatory markers as predictors of frailty. Clin Endocrinol. 2005;63:403–411
  49. Barzilay JI, Blaum C, Moore T, et al. Insulin resistance and inflammation as precursors of frailty: the Cardiovascular Health Study. Arch Intern Med. 2007;167:635–641
  50. Mourkioti F, Kratsios P, Luedde T, et al. Targeted ablation of IKK2 improves skeletal muscle strength, maintains mass, and promotes regeneration. J Clin Invest. 2006;116:2945–2954
  51. Visser M, Pahor M, Taaffe DR, et al. Relationship of interleukin-6 and tumor necrosis factor-{alpha} with muscle mass and muscle strength in elderly men and women: The Health ABC Study. J Gerontol A Biol Sci Med Sci. 2002;57:M326–M332
  52. Cesari M, Penninx BW, Pahor M, et al. Inflammatory markers and physical performance in older persons: the InCHIANTI study. J Gerontol A Biol Sci Med Sci. 2004;59:242–248
  53. Heber D, Ingles S, Ashley JM, et al. Clinical detection of sarcopenic obesity by bioelectrical impedance analysis. Am J Clin Nutr. 1996;64:472S–477S
  54. Kyle UG, Genton L, Hans D, et al. Age-related differences in fat-free mass, skeletal muscle, body cell mass and fat mass between 18 and 94 years. Eur J Clin Nutr. 2001;55:663–672
  55. de Rekeneire N, Peila R, Ding J, et al. Diabetes, hyperglycemia, and inflammation in older individuals: The Health, Aging and Body Composition study. Diabetes Care. 2006;29:1902–1908
  56. Zoico E, Di Francesco V, Guralnik JM, et al. Physical disability and muscular strength in relation to obesity and different body composition indexes in a sample of healthy elderly women. Int J Obes Relat Metab Disord. 2004;28:234–241
  57. Baumgartner RN, Wayne SJ, Waters DL, et al. Sarcopenic obesity predicts instrumental activities of daily living disability in the elderly. Obes Res. 2004;12:1995–2004
  58. Visser M, Kritchevsky SB, Goodpaster BH, et al. Leg muscle mass and composition in relation to lower extremity performance in men and women aged 70 to 79: the health, aging and body composition study. J Am Geriatr Soc. 2002;50:897–904
  59. Visser M, Goodpaster BH, Kritchevsky SB, et al. Muscle mass, muscle strength, and muscle fat infiltration as predictors of incident mobility limitations in well-functioning older persons. J Gerontol A Biol Sci Med Sci. 2005;60:324–333
  60. Deguchi K, Deguchi A, Wada H, Murashima S. Study of cardiovascular risk factors and hemostatic molecular markers in elderly persons. Semin Thromb Hemost. 2000;26:23–27
  61. Scarabin PY, Aillaud MF, Amouyel P, et al. Associations of fibrinogen, factor VII and PAI-1 with baseline findings among 10,500 male participants in a prospective study of myocardial infarction—the PRIME Study (Prospective Epidemiological Study of Myocardial Infarction). Thromb Haemost. 1998;80:749–756
  62. Hager K, Platt D. Fibrin degeneration product concentrations (D-dimers) in the course of ageing. Gerontology. 1995;41:159–165
  63. Tracy RP, Bovill EG, Fried LP, et al. The distribution of coagulation factors VII and VIII and fibrinogen in adults over 65 years (Results from the Cardiovascular Health Study). Ann Epidemiol. 1992;2:509–519
  64. Pieper CF, Rao KM, Currie MS, et al. Age, functional status, and racial differences in plasma D-dimer levels in community-dwelling elderly persons. J Gerontol A Biol Sci Med Sci. 2000;55:M649–M657
  65. Laharrague PF, Cambus JP, Fillola G, Corberand JX. Plasma fibrinogen and physiological aging. Aging (Milano). 1993;5:445–449
  66. Hager K, Felicetti M, Seefried G, Platt D. Fibrinogen and aging. Aging (Milano). 1994;6:133–138
  67. Takeshita K, Yamamoto K, Ito M, et al. Increased expression of plasminogen activator inhibitor-1 with fibrin deposition in a murine model of aging, “Klotho” mouse. Semin Thromb Hemost. 2002;28:545–554
  68. Conlan MG, Folsom AR, Finch A, et al. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis (The Atherosclerosis Risk in Communities (ARIC) Study). Thromb Haemost. 1993;70:380–385
  69. Tofler GH, Massaro J, Levy D, et al. Relation of the prothrombotic state to increasing age (from the Framingham Offspring Study). Am J Cardiol. 2005;96:1280–1283
  70. Cushman M, Yanez D, Psaty BM, et al. Association of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: the Cardiovascular Health Study (Cardiovascular Health Study Investigators). Am J Epidemiol. 1996;143:665–676
  71. Tracy RP, Arnold AM, Ettinger W, et al. The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the cardiovascular health study. Arterioscler Thromb Vasc Biol. 1999;19:1776–1783
  72. Cohen HJ, Harris T, Pieper CF. Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly. Am J Med. 2003;114:180–187
  73. McDermott MM, Greenland P, Green D, et al. D-dimer, inflammatory markers, and lower extremity functioning in patients with and without peripheral arterial disease. Circulation. 2003;107:3191–3198
  74. Wilson CJ, Cohen HJ, Pieper CF. Cross-linked fibrin degradation products (D-dimer), plasma cytokines, and cognitive decline in community-dwelling elderly persons. J Am Geriatr Soc. 2003;51:1374–1381
  75. Rafnsson SB, Deary IJ, Smith FB, et al. Cognitive decline and markers of inflammation and hemostasis: the Edinburgh Artery Study. J Am Geriatr Soc. 2007;55:700–707
  76. McDermott MM, Ferrucci L, Liu K, et al. D-dimer and inflammatory markers as predictors of functional decline in men and women with and without peripheral arterial disease. J Am Geriatr Soc. 2005;53:1688–1696
  77. Yamamoto K, Takeshita K, Shimokawa T, et al. Plasminogen activator inhibitor-1 is a major stress-regulated gene: implications for stress-induced thrombosis in aged individuals. Proc Natl Acad Sci U S A. 2002;99:890–895
  78. Yamamoto K, Shimokawa T, Yi H, et al. Aging and obesity augment the stress-induced expression of tissue factor gene in the mouse. Blood. 2002;100:4011–4018
  79. Kop WJ, Gottdiener JS, Tangen CM, et al. Inflammation and coagulation factors in persons>65 years of age with symptoms of depression but without evidence of myocardial ischemia. Am J Cardiol. 2002;89:419–424
  80. Panagiotakos DB, Pitsavos C, Chrysohoou C, et al. Inflammation, coagulation, and depressive symptomatology in cardiovascular disease-free people; the ATTICA study. Eur Heart J. 2004;25:492–499
  81. von Kanel R, Dimsdale JE, Mills PJ, et al. Effect of Alzheimer caregiving stress and age on frailty markers interleukin-6, C-reactive protein, and D-dimer. J Gerontol A Biol Sci Med Sci. 2006;61:963–969
  82. von Kanel R, Mills PJ, Fainman C, Dimsdale JE. Effects of psychological stress and psychiatric disorders on blood coagulation and fibrinolysis: a biobehavioral pathway to coronary artery disease?. Psychosom Med. 2001;63:531–544
  83. Walston J, McBurnie MA, Newman A, 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. 2002;162:2333–2341
  84. Folsom AR, Boland LL, Cushman M, et al. Frailty and risk of venous thromboembolism in older adults. J Gerontol A Biol Sci Med Sci. 2007;62:79–82
  85. Samad F, Yamamoto K, Loskutoff DJ. Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo (Induction by tumor necrosis factor-alpha and lipopolysaccharide). J Clin Invest. 1996;97:37–46
  86. Kilroy GE, Foster SJ, Wu X, et al. Cytokine profile of human adipose-derived stem cells: expression of angiogenic, hematopoietic, and pro-inflammatory factors. J Cell Physiol. 2007;212:702–709
  87. Birgel M, Gottschling-Zeller H, Rohrig K, Hauner H. Role of cytokines in the regulation of plasminogen activator inhibitor-1 expression and secretion in newly differentiated subcutaneous human adipocytes. Arterioscler Thromb Vasc Biol. 2000;20:1682–1687
  88. Rega G, Kaun C, Weiss TW, et al. Inflammatory cytokines interleukin-6 and oncostatin m induce plasminogen activator inhibitor-1 in human adipose tissue. Circulation. 2005;111:1938–1945
  89. Andus T, Geiger T, Hirano T, et al. Action of recombinant human interleukin 6, interleukin 1 beta and tumor necrosis factor alpha on the mRNA induction of acute-phase proteins. Eur J Immunol. 1988;18:739–746
  90. Castell JV, Gomez-Lechon MJ, David M, et al. Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS Lett. 1989;242:237–239
  91. Castell JV, Gomez-Lechon MJ, David M, et al. Recombinant human interleukin-6 (IL-6/BSF-2/HSF) regulates the synthesis of acute phase proteins in human hepatocytes. FEBS Lett. 1988;232:347–350
  92. Kaushansky K. Thrombopoietin. N Engl J Med. 1998;339:746–754
  93. Pang L, Weiss MJ, Poncz M. Megakaryocyte biology and related disorders. J Clin Invest. 2005;115:3332–3338
  94. Kaser A, Brandacher G, Steurer W, et al. Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood. 2001;98:2720–2725
  95. Mandl J, Csala M, Lerant I, et al. Enhancement of interleukin-6 production by fibrinogen degradation product D in human peripheral monocytes and perfused murine liver. Scand J Immunol. 1995;42:175–178
  96. Robson SC, Shephard EG, Kirsch RE. Fibrin degradation product D-dimer induces the synthesis and release of biologically active IL-1, IL-6, and plasminogen activator inhibitors from monocytes in vitro. Br J Haematol. 1994;86:322–326
  97. Ferrucci L, Corsi A, Lauretani F, et al. The origins of age-related proinflammatory state. Blood. 2005;105:2294–2299
  98. Ershler WB. Inflammation gone awry: aging or disease. Blood. 2005;105:2247

 Funding: This work was supported by the Intramural Research Program, National Institute on Aging (National Institutes of Health).

 Conflict of Interest: None.

 Authorship: All authors had access to the data and played a role in writing this manuscript.

PII: S0002-9343(09)00288-5

doi: 10.1016/j.amjmed.2009.01.030

The American Journal of Medicine
Volume 122, Issue 7 , Pages 605-613 , July 2009

Article Tools

* Image Usage & Resolution