Probing the relationship between insulin sensitivity and longevity using genetically modified mice.

Interference in insulin and/or insulin-like growth factor 1 (IGF-1) signaling can extend invertebrate life span, and interference in IGF-1 signaling can extend murine life span. Whether interference with murine insulin signaling, which can be diabetogenic and pathological, is also life-extending is controversial. We therefore measured life span in 3 murine strains genetically modified to reduce or increase insulin sensitivity. Mice with reduced insulin sensitivity were hemizygous for a null mutation in the insulin receptor (insulin receptor knockout mice; IRKO(+/-)). Mice with increased insulin sensitivity either had a null mutation of protein tyrosine phosphatase 1B (PTP-1B(-/-)) or overexpressed Peroxisome proliferator-activated receptor-α coactivator (PGC)-1α (PGC-1α(TG)). Life span of insulin insensitive IRKO(+/) mice was increased (males) or unaffected (females). Life spans of mice with increased insulin sensitivity were shortened overall (PTP-1B(-/-) mice) or partially (PGC-1α(TG): survival at the 25th percentile was reduced). These results show that insulin sensitivity in some murine genotypes is inversely related to longevity and provide further evidence for evolutionary conservation of this pathway as a modulator of longevity.