title: Inflammation and mortality in a frail mouse model.
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-10(tm/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-10(tm/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-10(tm/tm) mice. These findings provide additional rationale for the use of the IL-10(tm/tm) mouse as a model for frailty and for low-grade inflammatory pathway activation.
authors.affiliation: Brookdale Department of Geriatrics and Palliative Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Ko
authors.forename: Qilu
authors.initials: Q
authors.lastname: Yu
authors.forename: Qian-Li
authors.initials: QL
authors.lastname: Xue
authors.forename: Wenliang
authors.initials: W
authors.lastname: Yao
authors.forename: Cory
authors.initials: C
authors.lastname: Brayton
authors.forename: Huanle
authors.initials: H
authors.lastname: Yang
authors.forename: Neal
authors.initials: N
authors.lastname: Fedarko
authors.forename: Jeremy
authors.initials: J
authors.lastname: Walston
mesh_terms: D000375:Aging; D000818:Animals; D002423:Cause of Death; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000097:blood* / Q000235:genetics; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000401:mortality*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D016207:Cytokines