Mechanisms of prolonged longevity: Mutants, knock-outs, and caloric restriction

Hypopituitary dwarf mice deficient in growth hormone (GH), prolactin (PRL), and thyrotropin (TSH) are remarkably long-lived. Similar extension of longevity was reported in mice with GH resistance produced by knock-out of GH receptor gene (GHR-KO mice). Many characteristics of long-lived mutant and GHR-KO mice resemble those of normal (wild-type) animals subjected to chronic caloric restriction (CR). These characteristics include reduced plasma levels of insulin-like growth factor-I (IGF-I) with the consequent reductions in growth and body size, delayed puberty, reduced plasma levels of glucose and insulin, and markedly increased sensitivity to insulin actions. However, long-lived mutant and GHR-KO mice differ from CR animals with respect to plasma corticosterone levels, spontaneous locomotor activity, and body composition. These differences, along with studies of the effects of CR in dwarf mice, suggest that these long-lived mutants, as well as the GHR-KO mice are not CR mimetics. It is suggested that increased sensitivity to insulin and reduced activity of the somatotropic axis constitute likely mechanisms of delayed aging in each of these models of life extension in mammals.