Aging is the strongest risk factor for most forms of cancer, however, little is known regarding the mechanisms involved. Dietary methionine restriction (MR) has been found to delay the aging process and enhance longevity up to 40% in rats without restriction in energy intake. In addition, MR inhibits numerous key factors involved in the metabolic decline of aging characterized by changes in fat distribution, obesity and insulin resistance. Recent studies have provided compelling evidence linking obesity and insulin resistance with enhanced susceptibility to cancer at many sites with key fat-derived cytokines (adipocytokines) playing an important role. We hypothesize that MR inhibits aging/insulin resistance-related changes in adipocytokine production and reduces the risk for cancer development. To test this, male F344 rats were fed control (CF, 0.86% Met) or experimental (MR, 0.17% Met) diets beginning at 6 weeks of age until sacrifice at approximately 30 months of age. Histopathologic analyses were performed to identify the incidence and progression of common aging-related tumors. Blood was obtained and plasma levels of adipocytokines (adiponectin and leptin), glucose and insulin were determined and correlated. Testicular tumors were the most common neoplasm observed occurring in 88% of CF animals. MR resulted in a significant reduction in testicular tumor incidence (22% of MR rats, p<0.04) with a delay in the disease progression from the hyperplastic stage. The levels of plasma adiponectin (reduced in obese/diabetic animals and humans), were increased 3-fold in MR rats. Adiponectin levels were inversely correlated with the levels of blood glucose, insulin and leptin. These results suggest that MR may lead to metabolic and cellular changes providing protection against aging-related tumorigenesis through mechanisms that promote a lifelong insulin sensitive phenotype. Further studies to elucidate the specific mechanisms involved are currently underway.