Age is a major determinant of circulating Insulin-like Growth Factor-I (IGF-I) levels. In healthy populations levels of IGF-I markedly differ between individuals, but total IGF-I, IGFBP-3, and their ratio within one individual show only small changes with age over time. In many experimental models an increased longevity has been found with downregulation of the growth hormone (GH)/IGF-I system. However, a relationship between low IGF-I and longevity is often only observed in female animals. In contrast, in humans low IGF-I has not consistently been found to be associated with longevity. Low protein intake during middle age followed by moderate to high protein consumption in old adults may optimize longevity through a process that may involve regulation of circulating IGF-I. Changes of IGF-I levels over time in an individual may provide more insights about the relevance of IGF-I for lifespan of that individual than measuring IGF-I once at baseline. For each individual there probably is a specific optimal age-dependent 'setpoint’ for the GH/IGF-I system which co-determines survival. Local (paracrine) IGF-I actions may induce effects independently from systemic circulating IGF-I. Therefore, in order to obtain an overall view about the role of IGF-I in the endocrinology of aging it is necessary to study both paracrine and systemic (endocrine) IGF-I-mediated effects.