Hormonal signals from adipose tissue regulate energy homeostasis but may also be involved in the anti-aging effects of caloric restriction. The purpose of the current study was the investigation of age-dependent effects of caloric restriction on the release of adiponectin, on the expression and activation of adiponectin-related signaling and on parameters of altered insulin sensitivity. In young and in senescent rats, 2 months moderate caloric restriction reduces serum leptin and insulin (young: -50%; old: -30%) suggesting increased insulin sensitivity. However, the same diet enhances serum adiponectin in young (+60%) but not in senescent (+2%, n=NS) rats. Similarly, adiponectin expression (visceral fat) and muscular AdipoR1/2 expression are induced in young rats but not in senescent rats. The locally produced adiponectin paralogs CTRP2/7 are elevated in muscular tissues of old animals (CTRP2 protein: +40%;CTRP7 protein: +50%) and further induced by caloric restriction but this does not result in an increased activation of their downstream target AMPK. Thus, aging is associated with a partial loss of adiponectin inducibility following moderate caloric restriction. This loss is not sufficiently compensated by the locally induced adiponectin paralogs CTRP2/7, although caloric restriction results in increased insulin sensitivity in young and in senescent animals. Thus, the improvement in insulin sensitivity appears to be independent of adiponectin induction by caloric restriction in this model.