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Inflammation and mortality in a frail mouse model

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Abstract

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.

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Acknowledgments

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.

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Authors and Affiliations

  1. Brookdale Department of Geriatrics and Palliative Medicine, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Fred Ko

  2. Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, 21224, USA

    Qilu Yu, Qian-Li Xue, Wenliang Yao, Huanle Yang, Neal Fedarko & Jeremy Walston

  3. Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Cory Brayton

  4. Johns Hopkins Asthma and Allergy Center, Suite 1A.62, 5501 Bayview Circle, Baltimore, MD, 21224, USA

    Jeremy Walston

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  1. Fred Ko
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  2. Qilu Yu
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  3. Qian-Li Xue
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  4. Wenliang Yao
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  8. Jeremy Walston
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Correspondence to Jeremy Walston.

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Ko, F., Yu, Q., Xue, QL. et al. Inflammation and mortality in a frail mouse model. AGE 34, 705–715 (2012). https://doi.org/10.1007/s11357-011-9269-6

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  • DOI: https://doi.org/10.1007/s11357-011-9269-6

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