The aging process is accompanied by increased expression of several acute phase response (APR) genes, such as interleukin-6 (IL-6), in the absence of disease or unusual extrinsic stress by an unknown mechanism. The Free Radical Theory of Aging, which promotes that oxidative stress increases with age, may provide some clues to this phenomenon. Specifically, reactive oxygen intermediates (ROI) act as second messengers culminating in activation of signal transduction and transcription factor activity. Thus, it follows that age-associated oxidative stress can mediate gene expression. The caloric restriction (CR) paradigm provides additional support for this postulation. Specifically, CR, which decreases oxidative stress, also delays the appearance of age-associated IL-6 expression. The working hypotheses for this application are: 1) The aging process increases IL-6 expression through oxidative stress-induced signal transduction; and 2) CR delays age-related IL-6 expression through antagonizing oxidative stress. The investigators will explore their hypotheses using dysregulation of IL-6 gene expression as a model of age's influence on APR gene expression in skeletal muscle (primarily a post-mitotic tissue). To accomplish this, they will perform the following Specific Aims: 1) Determine how oxidative stress induces the IL-6 promoter in vitro at the transcriptional factor level. 2) Identify the signal transduction pathways that oxidative stress activates to induce the IL-6 promoter in vitro. To test if these mechanisms are active with age in vivo, they will use 7, 14, and 21 month old mice that are transgenic for the IL-6 promoter driving the luciferase reporter cDNA in the following Aims: 3) Evaluate the role of oxidative stress in IL-6 promoter activation with aging in vivo. 4) Identify if CR antagonizes oxidative stress-induced IL-6 gene expression with age. In the in vivo studies, the investigators will evaluate both basal and exercise and tumor necrosis factor-induced oxidative stress. In summary, these studies are designed to elucidate the mechanism of oxidative stress-mediated gene transcription in the context of aging. The broad implications of this work include both; (1) understanding the basic molecular biology of gene expression with aging and (2) developing molecular interventions to diminish age-associated dysregulation of gene expression which contribute to geriatric disorders.
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