Reduced insulin and IGF-1 signalling synergistically extend healthspan in male mice

Abstract Reduced IGF-1 signalling is an evolutionarily conserved mediator of longevity, yet the magnitude of this effect is substantially larger in organisms retaining a common insulin and IGF-1 receptor. Whether this discrepancy reflects the failure to simultaneously reduce IGF-1 and insulin signalling in mammalian model systems remains unexplored. Moreover, studies of invertebrates cannot ascertain whether substantial effects upon lifespan are associated with preserved cognitive performance, a crucial component of healthspan(definition). We compared the healthspan of male mice with haploinsufficiency of the insulin receptor (IRKO), IGF-1 receptor (IGF-1RKO), or both (DKO), with wildtype (WT) littermates. DKO mice survived longer than WT, with IRKO and IGF-1RKO being intermediate. At 2 years of age, DKO also exhibited preserved nesting behaviour in contrast with all other genotypes. Differential insulin sensitivity or weight gain during ageing did not explain the preserved healthspan of DKO, since these were comparable to IRKO littermates. These data provide the first demonstration that reduced insulin and IGF-1 signalling have synergistic effects upon healthspan in a mammalian model system, suggesting future mechanistic and translational studies should target insulin and IGF-1 signalling.