, Volume 34, Issue 3, pp 705–715 | Cite as

Inflammation and mortality in a frail mouse model

  • Fred Ko
  • Qilu Yu
  • Qian-Li Xue
  • Wenliang Yao
  • Cory Brayton
  • Huanle Yang
  • Neal Fedarko
  • Jeremy Walston


Mice homozygous for targeted deletion of the interleukin 10 gene (Il-10) have been partially characterized as a model for human frailty. These mice have increased serum interleukin (IL)-6 in midlife, skeletal muscle weakness, and an altered skeletal muscle gene expression profile compared to age and sex-matched C57BL/6 (B6) control mice. In order to further characterize for use as a frailty model, we evaluated the evolution of inflammatory pathway activation, endocrine change, and mortality in these mice. Serum was collected in groups of age- and sex-matched B6.129P2-Il10 tm1Cgn /J (IL-10tm/tm) mice and B6 control mice at age 12, 24, 48, 72, and 90 weeks. Cytokines including IL-6, interleukin 1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), chemokine (C-X-C motif) ligand 1 (KC), IL-12, and IL-10 were measured using electro-chemiluminescent multiplex immunoassay and insulin-like growth factor 1 (IGF-1) was measured using solid-phase enzyme-linked immunosorbent assay. A separate longitudinal cohort was monitored from age 35 weeks to approximately 100 weeks. Survival was evaluated by Kaplan–Meier survival estimates and detailed necropsy information was gathered in a subset of mice that died or were sacrificed. In IL-10tm/tm mice compared to B6 controls, serum IL-6, IL-1β, TNF-α, IFN-γ, KC levels were significantly elevated across the age groups, serum mean IGF-1 levels were higher in the 48-week-old groups, and overall mortality rate was significantly higher. The quadratic relationship between IGF-1 and age was significantly different between the two strains of mice. Serum IL-6 was positively associated with IGF-1 but the effect was significantly larger in IL-10tm/tm mice. These findings provide additional rationale for the use of the IL-10tm/tm mouse as a model for frailty and for low-grade inflammatory pathway activation.


IGF-1 IL-6 IL-10 C57BL/6 Inflammation Mortality Frailty 



This research was supported by the National Institute on Aging, Claude D. Pepper Older Americans Independence Centers, grant P30 AG021334, National Institute on Aging, grant R21-AG025143, and Beeson AFAR award.


  1. Bartke A (2008) Impact of reduced insulin-like growth factor-1/insulin signaling on aging in mammals: novel findings. Aging Cell 7(3):285–290PubMedCrossRefGoogle Scholar
  2. Brown-Borg HM, Borg KE, Meliska CJ, Bartke A (1996) Dwarf mice and the ageing process. Nature 384(6604):33PubMedCrossRefGoogle Scholar
  3. Bodell PW, Kodesh E, Haddad F, Zaldivar FP, Cooper DM, Adams GR (2009) Skeletal muscle growth in young rats is inhibited by chronic exposure to IL-6 but preserved by concurrent voluntary endurance exercise. J Appl Physiol 106(2):443–453PubMedCrossRefGoogle Scholar
  4. Cappola AR, Xue QL, Ferrucci L, Guralnik JM, Volpato S, Fried LP (2003) Insulin-like growth factor I and interleukin-6 contribute synergistically to disability and mortality in older women. J Clin Endocrinol Metab 88(5):2019–2025PubMedCrossRefGoogle Scholar
  5. Cesari M, Penninx BW, Pahor M, Lauretani F, Corsi AM, Rhys Williams G et al (2004) Inflammatory markers and physical performance in older persons: the InCHIANTI study. J Gerontol A Biol Sci Med Sci 59(3):242–248PubMedCrossRefGoogle Scholar
  6. Chiba T, Yamaza H, Shimokawa I (2007) Role of insulin and growth hormone/insulin-like growth factor-I signaling in lifespan extension: rodent longevity models for studying aging and calorie restriction. Curr Genomics 8(7):423–428PubMedCrossRefGoogle Scholar
  7. Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E et al (2001) Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292(5514):104–106PubMedCrossRefGoogle Scholar
  8. Cohen HJ, Harris T, Pieper CF (2003) Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly. Am J Med 114(3):180–187PubMedCrossRefGoogle Scholar
  9. Chomarat P, Rissoan MC, Banchereau J, Miossec P (1993) Interferon gamma inhibits interleukin 10 production by monocytes. P J Exp Med 177(2):523–527CrossRefGoogle Scholar
  10. D’Andrea A, Aste-Amezaga M, Valiante NM, Ma X, Kubin M, Trinchieri G (1993) Interleukin 10 (IL-10) inhibits human lymphocyte interferon γ-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med 178:1041PubMedCrossRefGoogle Scholar
  11. Ferrucci L, Harris TB, Guralnik JM, Tracy RP, Corti MC, Cohen HJ et al (1999) Serum IL-6 level and the development of disability in older persons. J Am Geriatr Soc 47(6):639–646PubMedGoogle Scholar
  12. Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A (1991) IL-10 inhibits cytokine production by activated macrophages. J Immunol 147:3815PubMedGoogle Scholar
  13. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J et al (2001) Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56(3):M146–M156PubMedCrossRefGoogle Scholar
  14. Guarente L, Kenyon C (2000) Genetic pathways that regulate ageing in model organisms. Nature 408(6809):255–262PubMedCrossRefGoogle Scholar
  15. Haddad F, Zaldivar F, Cooper DM, Adams GR (2005) IL-6-induced skeletal muscle atrophy. J Appl Physiol 98(3):911–917PubMedCrossRefGoogle Scholar
  16. Hanada T, Yoshimura A (2002) Regulation of cytokine signaling and inflammation. Cytokine Growth Factor Rev 13(4–5):413–421PubMedCrossRefGoogle Scholar
  17. Harris TB, Ferrucci L, Tracy RP, Corti MC, Wacholder S, Ettinger WH Jr et al (1999) Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 106(5):506–512PubMedCrossRefGoogle Scholar
  18. Kelley KW (2004) From hormones to immunity: the physiology of immunology. Brain Behav Immun 18(2):95–113PubMedCrossRefGoogle Scholar
  19. Kelley KW, Weigent DA, Kooijman R (2007) Protein hormones and immunity. Brain Behav Immun 21(4):384–392PubMedCrossRefGoogle Scholar
  20. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75(2):263–274PubMedCrossRefGoogle Scholar
  21. Leng S, Chaves P, Koenig K, Walston J (2002) Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study. J Am Geriatr Soc 50(7):1268–1271PubMedCrossRefGoogle Scholar
  22. Leng SX, Cappola AR, Andersen RE, Blackman MR, Koenig K, Blair M et al (2004) Serum levels of insulin-like growth factor-I (IGF-I) and dehydroepiandrosterone sulfate (DHEA-S), and their relationships with serum interleukin-6, in the geriatric syndrome of frailty. Aging Clin Exp Res 16(2):153–157PubMedGoogle Scholar
  23. Leng SX, McElhaney JE, Walston JD, Xie D, Fedarko NS, Kuchel GA (2008) ELISA and multiplex technologies for cytokine measurement in inflammation and aging research. J Gerontol A Biol Sci Med Sci 63:879–884PubMedCrossRefGoogle Scholar
  24. Leng SX, Xue QL, Tian J, Huang Y, Yeh SH, Fried LP (2009) 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 44:511–516PubMedCrossRefGoogle Scholar
  25. Masternak MM, Al-Regaiey KA, Del Rosario Lim MM, Jimenez-Ortega V, Panici JA, Bonkowski MS et al (2005) Effects of caloric restriction on insulin pathway gene expression in the skeletal muscle and liver of normal and long-lived GHR-KO mice. Exp Gerontol 40(8–9):679–684PubMedCrossRefGoogle Scholar
  26. Miller RA (2009) The aging immune system: primer and prospectus. Science 273:70–74CrossRefGoogle Scholar
  27. Moore KW, O’Garra A, De Waal Malefyt R, Vieira P, Mosmann TR (1993) Interleukin-10. Annu Rev Immunol 11:165PubMedCrossRefGoogle Scholar
  28. Mourkioti F, Rosenthal N (2005) IGF-1, inflammation and stem cells: interactions during muscle regeneration. Trends Immunol 26(10):535–542PubMedCrossRefGoogle Scholar
  29. Rennick D, Davidson N, Berg D (1995) Interleukin-10 gene knock-out mice: a model of chronic inflammation. Clin Immunol Immunopathol 76(3 Pt 2):S174–S178PubMedCrossRefGoogle Scholar
  30. Salminen A, Kaarniranta K (2010) Insulin/IGF-1 paradox of aging: regulation via AKT/IKK/NF-kappaB signaling. Cell Signal 22(4):573–577PubMedCrossRefGoogle Scholar
  31. Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS (2001) A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292(5514):107–110PubMedCrossRefGoogle Scholar
  32. Tatar M (2009) Can we develop genetically tractable models to assess healthspan (rather than life span) in animal models? J Gerontol A Biol Sci Med Sci 64:161–163PubMedCrossRefGoogle Scholar
  33. Tripp CS, Wolf SF, Unanue ER (1993) Interleukin 12 and tumor necrosis factor α are costimulators of interferon γ production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proc Natl Acad Sci USA 90:3725PubMedCrossRefGoogle Scholar
  34. Varadhan R, Seplaki CL, Xue QL, Bandeen-Roche K, Fried LP (2008) Stimulus-response paradigm for characterizing the loss of resilience in homeostatic regulation associated with frailty. Mech Ageing Dev 129:666–670PubMedCrossRefGoogle Scholar
  35. Walston J, McBurnie MA, Newman A, Tracy RP, Kop WJ, Hirsch CH et al (2002) Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study. Arch Intern Med 162(20):2333–2341PubMedCrossRefGoogle Scholar
  36. Walston J, Hadley EC, Ferrucci L, Guralnik JM, Newman AB, Studenski SA et al (2006) 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 54(6):991–1001PubMedCrossRefGoogle Scholar
  37. Walston J, Fedarko N, Yang H, Leng S, Beamer B, Espinoza S et al (2008) The physical and biological characterization of a frail mouse model. J Gerontol A Biol Sci Med Sci 63(4):391–398PubMedCrossRefGoogle Scholar
  38. Wolf E, Kahnt E, Ehrlein J, Hermanns W, Brem G, Wanke R (1993) Effects of long-term elevated serum levels of growth hormone on life expectancy of mice: lessons from transgenic animal models. Mech Ageing Dev 68(1–3):71–87PubMedCrossRefGoogle Scholar
  39. Yao X, Li H, Leng SX (2011) Inflammation and immune system alterations in frailty. Clin Geriatr Med 27:79–87PubMedCrossRefGoogle Scholar
  40. Yuan R, Tsaih SW, Petkova SB, de Evsikova CM, Xing S, Marion MA et al (2009) Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell 8(3):277–287PubMedCrossRefGoogle Scholar

Copyright information

© American Aging Association 2011

Authors and Affiliations

  • Fred Ko
    • 1
  • Qilu Yu
    • 2
  • Qian-Li Xue
    • 2
  • Wenliang Yao
    • 2
  • Cory Brayton
    • 3
  • Huanle Yang
    • 2
  • Neal Fedarko
    • 2
  • Jeremy Walston
    • 2
    • 4
  1. 1.Brookdale Department of Geriatrics and Palliative MedicineMount Sinai School of MedicineNew YorkUSA
  2. 2.Division of Geriatric Medicine and GerontologyJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Molecular and Comparative PathobiologyJohns Hopkins University School of MedicineBaltimoreUSA
  4. 4.Johns Hopkins Asthma and Allergy CenterBaltimoreUSA

Personalised recommendations