Mutations in growth signaling pathways extend life span, as well as protect against age-dependent DNA damage in yeast and decrease
insulin resistance and
cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian individuals who carry mutations in the
growth hormone receptor (GHR) gene that lead to severe GHR and
IGF-1 (insulin-like growth factor-1) deficiencies. We combined this information with surveys to identify the cause and age of death for individuals in this community who died before this period. The individuals with GHR deficiency exhibited only one nonlethal
malignancy and no cases of diabetes, in contrast to a prevalence of 17% for
cancer and 5% for diabetes in control subjects. A possible explanation for the very low incidence of
cancer was suggested by in vitro studies: Serum from subjects with GHR deficiency reduced DNA breaks but increased apoptosis in human mammary epithelial cells treated with
hydrogen peroxide. Serum from GHR-deficient subjects also caused reduced expression of RAS, PKA (
protein kinase A), and TOR (target of
rapamycin) and up-regulation of SOD2 (
superoxide dismutase 2) in treated cells, changes that promote cellular protection and life-span extension in model organisms. We also observed reduced
insulin concentrations (1.4 μU/ml versus 4.4 μU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment-
insulin resistance) index (0.34 versus 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher
insulin sensitivity, which could explain the absence of diabetes in these subjects. These results provide evidence for a role of evolutionarily conserved pathways in the control of aging and disease burden in humans.