Endocrine Abstracts

Complex interactions between aging and the endocrine system include an important role of hormones in mediating effects of genotype on longevity. In Caenorhabditis elegans and Drosophila melanogaster, striking extension of life span can be produced by targeted disruption (knock out, KO) of genes that control signaling pathways homologous to insulin/insulin-like growth factor signaling in mammals. In the mouse, Mus musculus, longevity is greatly increased by spontaneous and experimentally-induced mutations that affect the somatotropic axis and, indirectly, insulin signaling. These mutations include Ames dwarf (Prop1df) and Snell dwarf (Pit1dw) that interfere with development of three cell lineages in the anterior pituitary during fetal life, leading to deficiency of growth hormone (GH), prolactin, and thyrotropin. The importance of GH deficiency in increasing longevity of these animals is suspected from the comparable life extension in GH receptor KO (Laron dwarf) mice in which primary endocrine defect is limited to GH resistance. Moreover, little (GHRHRlit) mice with isolated GH deficiency live longer than normal mice if their obesity is prevented by low fat diet. GH deficiency or resistance leads to alterations of insulin release and its actions. In dwarf and GHR-KO mice, insulin signaling is reduced and sensitivity of the liver to insulin is enhanced while glucose tolerance is, unexpectedly, attenuated. Phenotypic characteristics of long-lived mutant mice including concomitant reduction in plasma insulin and glucose levels, reduced growth and adult body size, delayed puberty, and reduced fertility resemble alterations in genetically normal (wild type) mice subjected to caloric restriction (CR). However, there is evidence to suggest that these mutants are not CR mimetics. Mechanisms ultimately responsible for delayed aging and prolonged longevity of dwarf and GHR-KO mice remain to be identified and almost certainly include reduced oxidative damage to macromolecules. (Supported by NIH and Illinois CFAR.)