Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends Lifespan

Abstract

The causal relationships between insulin levels, insulin resistance, and longevity are not fully elucidated. Genetic downregulation of insulin/insulin-like growth factor 1 (Igf1) signaling components can extend invertebrate and mammalian lifespan, but insulin resistance, a natural form of decreased insulin signaling, is associated with greater risk of age-related disease in mammals. We compared Ins2 mice to Ins2 littermate controls, on a genetically stable Ins1 null background. Proteomic and transcriptomic analyses of livers from 25-week-old mice suggested potential for healthier aging and altered insulin sensitivity in Ins2 mice. Halving Ins2 lowered circulating insulin by 25%-34% in aged female mice, without altering Igf1 or circulating Igf1. Remarkably, decreased insulin led to lower fasting glucose and improved insulin sensitivity in aged mice. Moreover, lowered insulin caused significant lifespan extension, observed across two diverse diets. Our study indicates that elevated insulin contributes to age-dependent insulin resistance and that limiting basal insulin levels can extend lifespan.

Fructose metabolism and metabolic disease

“…These results are consistent with dietary intervention studies in humans indicating that either eucaloric substitution or hypercaloric addition of fructose may have more significant effects on hepatic insulin resistance than peripheral insulin resistance (157). However, as hyperinsulinemia itself can induce peripheral insulin resistance (162,163), we speculate that chronic hyperinsulinemia that compensates for fructose-induced glucose production may subsequently lead to peripheral insulin resistance. This hypothesis remains to be tested experimentally.…”

Does insulin signalling decide glucose levels in the fasting steady state?

“…A double knockout of both the genes results in death, but ablation of either of the genes does not alter the glucose tolerance significantly suggesting redundancy (90). There are studies in which one gene is completely knocked out and the other one is a heterozygote (90)(91)(92)(93)(94). Reduced insulin gene dosage did not consistently result into fasting hyperglycemia in these studies although it offered protection against some of the effects of hyperinsulinemia.…”

Reducing insulin via conditional partial gene ablation in adults reverses diet‐induced weight gain

“…Studies where individualized dietary responses are assessed (52) and mechanistically defined will be useful for the design of personalized nutrigenomic strategies. Approaches that physiologically modulate insulin levels may also have therapeutic utility beyond weight loss, including in the improvement of insulin sensitivity, and perhaps even longevity (53). …”