New Insulin Receptor Mutations Mimic Long-Lived Mice Without Causing Diabetes

Reducing insulin/IGF signaling is one of the most reproducible ways to extend lifespan across species, but the strategy has a critical flaw: it typically causes insulin resistance, stunted growth, and reproductive impairment — problems that limit its translational potential. This study sought to sidestep those trade-offs by introducing a gain-of-function point mutation, originally discovered in Drosophila, into mammalian receptors.

The team generated two knock-in C57BL/6J mouse strains bearing an arginine-to-cysteine substitution in the kinase insert domain (KID) of either the insulin receptor (IR R1109C) or IGF-1 receptor (IGF-1R R1096C). This residue is conserved across species, and in flies the analogous substitution (dInr R1466C) robustly extends lifespan in both sexes without impairing insulin sensitivity, body size, or fecundity. The mouse models were studied at heterozygosity — one mutant allele paired with one wild-type allele — to mirror the Drosophila heterozygote context.

Heterozygous IR and IGF-1R KID mice showed largely normal growth, body composition, and metabolic rates. Female IGF-1R heterozygotes were modestly lighter (12.7%) with slightly lower lean and fat mass, but males were indistinguishable from wild-type. Indirect calorimetry revealed normal respiratory exchange ratios (~0.80–0.85), energy expenditure, and physical activity. Crucially, glucose and insulin tolerance tests were normal in both strains and both sexes, confirming preserved insulin sensitivity — a stark departure from classical IIS mutants.

At 4 months, both strains showed variable but noteworthy hormonal shifts. Female IR heterozygotes had elevated adiponectin and FGF21 — two hormones repeatedly linked to metabolic health, longevity, and delayed aging in mice and humans. IGF-1R heterozygotes of both sexes showed reduced circulating IGF-1 and leptin. These endocrine signatures closely resemble those of established long-lived mouse models such as Ames dwarf and caloric restriction paradigms. A transcriptomic biological age clock applied to liver tissue showed significantly reduced biological age specifically in IGF-1R female heterozygotes, suggesting possible tissue-level aging deceleration.

In parallel human cell experiments, mutant receptors formed functional heterodimers with wild-type protomers. These heterodimers retained full insulin- and IGF-1-stimulated phosphorylation of Akt — the canonical survival and metabolic effector — but showed blunted ERK phosphorylation, particularly in IGF-1R heterodimers. This biased signaling pattern may explain how the KID mutation promotes longevity-associated outcomes without disrupting metabolic homeostasis. The authors conclude that the KID domain represents a novel modulatory site in mammalian IIS receptors that warrants full lifespan studies.