Starting from young to very old subjects, aging is associated with a progressive remodeling. Such an age-dependent remodeling process mainly affects anthropometrics, endocrine and thus, also metabolic factors. Interestingly, it occurs in some individuals successfully, while in others unsuccessfully. Centenarians in good health conditions are a very selected group of subjects representing an exceptional condition. Why the centenarians reach the extreme human life span is still unknown. Thus, in this article we will review the best known causes of age-related insulin resistance, outline the main metabolic differences between aged subjects and healthy centenarians, underline the clinical relevance of insulin resistance in the elderly and finally, we will try to propose a unifying hypothesis for explaining the development of insulin resistance with aging.