Development of a Mouse Model for Frailty
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DESCRIPTION (provided by applicant): The goal of this study is to establish a frail mouse model that can be utilized in future etiologic and intervention studies of the geriatric syndrome of frailty. The phenotypic characteristics sought in this model include age related declines in activity, muscle strength, and weight, and increased markers systemic inflammation as characterized by increased serum levels of the inflammatory cytokine IL-6. The IL-10tm/tm mouse has a decreased ability to counter NFkB related inflammatory activation, and our pilot data that shows that the IL-10tm/tm mouse develops age-related physical and physiological features that are consistent with frailty. We hypothesize that the IL-10tm/tm mouse will develop phenotypic alterations with increasing age consistent with human frailty as compared to age and gender matched C57Bl/6J control mice. We further hypothesize that these changes will result from the chronic activation of inflammatory pathways. In the first specific aim, we propose to longitudinally and cross-sectionally compare IL-10tm/tm mice with their age and gender matched C57Bl/6J control strain through assessments of muscle strength, balance, weight, and activity, complete blood counts, inflammatory marker profile, IGF-1 levels, skeletal muscle gene expression. In specific aim 2, we propose to develop detailed studies of the causes of co-morbidities and mortality and compare them between IL-10tm/tm and control strain. In specific aim three, we propose to extend our preliminary findings of altered mitochondrial related gene expression to explore mitochondrial function at different ages in skeletal muscle. The establishment of a frail mouse model caused by chronic activation of inflammatory pathways will greatly facilitate the ability of investigators to perform both etiologic and intervention studies of frailty, and enable a deeper biological understanding of incumbent co-morbidities and vulnerabilities of frail, older adults. The purpose of this project is to develop a frail mouse model that can be utilized to better understand the biological changes that develop with frailty. We will study the physical, physiological and molecular characteristics of the IL-10tm/tm mouse strain and compare it to a control mouse strain at several age points. We expect to find that the frail mouse has higher levels of inflammatory markers, muscle weakness, and altered gene expression as it gets older, similar to what is found in frail, older humans.
