Currently, cancer is the second leading cause of death in the U.S, responsible for 1 in 4 deaths. Scientific evidence has suggested that obesity may influence cancer biology. A salient potential biologic mechanism via which obesity may promote proliferation of cancer cells and impact cancer progression is metabolic syndrome, and its associated disturbances in the insulin/insulin-like growth factor (IGF-1) axis, leptin metabolism, and inflammation. Although several potential biological mechanisms supporting the role of metabolic syndrome on cancer mortality have been hypothesized and confirmed by animal studies, these relationships have not yet been fully characterized in humans, and remain mostly indirect. Previous studies suggest that lifestyle interventions such as healthier diet and physical activity, which reduce insulin resistance, may also reduce the risk of some cancers. However, human data on this topic are sparse and the magnitude of the effects is not well quantified. This proposed longitudinal cohort study plans to address these existing knowledge gaps. The primary aims are designed to quantify the impact of metabolic syndrome and biomarkers associated with it on cancer mortality. The secondary objectives are designed to evaluate whether three lifestyle attributes: 1) regular physical activity, 2) high caloric intake, or 3) use of non-steroidal anti-inflammatory drugs, can modify the risk of cancer death among individuals with metabolic syndrome. We plan to use Cox-proportional hazard models to evaluate these associations among approximately 12,000+ adults, from the Third National Health and Nutrition Examination Survey (1988-94), a nationally representative sample of the US population. Cause of death for the study cohort has been prospectively ascertained through year 2000. The availability of anthropometric measurements and blood data provide the opportunity to accurately ascertain whether individuals have metabolic syndrome. Further, the availability of blood IGF-1, its binding protein IGFBP-3, leptin, C-reactive protein, a marker of inflammation, provide a unique opportunity to investigate the possible mechanisms that link metabolic syndrome and cancer mortality. Additionally, histories of diet, physical activity and aspirin use, and non-steroidal anti-inflammatory drug, will enable us to explore how the relationships of cancer mortality and metabolic syndrome, vary with these lifestyle behaviors. To our knowledge, this is the first well-powered, national study to address the interrelationships of the potential biological pathways of metabolic syndrome in the context of cancer mortality. The results of this study will facilitate future intervention trials and ultimately aid in the design of individualized treatment. Lay abstract - This proposed study, utilizing a national sample of over 12,000 adults, is designed to identify potential pathways and interventions that may be used to reduce the toll of obesity-related cancer deaths. Metabolic syndrome, a high-risk condition for cancer progression, is prevalent among 1 in 4 Americans, and may have predictive value for cancer mortality. This research aimed at investigating metabolic syndrome and its associated biomarkers, in relation with cancer mortality, will aid in risk-stratification of patients and help physicians in designing individualized target therapies. This study will also generate preliminary data for intervention studies involving physical activity/diet, as well as pharmacological trials using anti-inflammatory drugs, in relation with cancer biology. [unreadable] [unreadable] [unreadable]