Late Life IGF-1 Inhibition Modestly Extends Life in Female Mice Only
One of the most studied areas of metabolism and its interaction with aging involves the activities of, and relationships between, IGF-1, insulin, growth hormone, and their cell surface receptors, all of which are among the mechanisms strongly influenced by calorie restriction. Genetic engineering to disable growth hormone or its receptor produces dwarf mice that live 60% longer, and IGF-1 can be similarly manipulated to produce a less exceptional life extension. It is worth noting that the equivalent growth hormone loss of function mutants in our species do not live 60% longer, though they may be modestly more resistant to age-related disease. Short-lived species have evolved a far greater plasticity of life span in response to calorie restriction or interventions that directly manipulate the related cellular mechanisms. Development of therapies based upon these findings seem unlikely to produce sufficiently sizable effects on human health to justify the investment, given the range of better alternatives on the table.
Diminished growth hormone (GH) and insulin/insulin-like growth factor-1 (IGF-1) signaling extends lifespan in many laboratory models. Likewise, several dwarf models, including Ames, Snell and growth hormone receptor knockout (GHRKO) mice, are exceptionally long lived. A specific role for IGF-1 receptor (IGF-1R) signaling in the mediation of mammalian longevity was first established in IGF-1R haploinsufficient mice, which lived 33% longer than controls, but unlike other models of reduced somatotropic signaling, this effect was female specific. This unique sex difference was subsequently confirmed in two follow-up studies, though with more modest reported improvements in female lifespan, while a life shortening effect was observed in males. The underlying mechanisms linking reduced IGF-1 signaling to improved mammalian lifespan is thought to involve improved stress defenses and lower risk for proliferative diseases, though the reason for sex differences in this response remains unresolved.
Several examples have also now emerged suggesting the GH/IGF-1 signaling pathway is relevant to human aging, including the discovery of functional mutations in the IGF-1R gene in individuals with exceptional longevity, resulting in relative IGF-1 resistance, and in subjects lacking functional GH receptors (Laron dwarfs). Remarkably, low IGF-1 levels also predict better survival in nonagenarians, and similar to lessons learned in IGF-1R heterozygous mice, this effect is female specific. Thus, given the accumulating evidence across species implicating this pathway as integral to aging and its associated diseases, the development of therapeutics aimed at modulating IGF-1 signaling in humans could prove highly effective as a translational tool to delay aging. However, given that previous demonstrations of longevity resulting from disruption of this pathway occurred either at conception or in young adulthood, whether benefits can be achieved by targeting this pathway later in life is unclear.
Anti-IGF-1 receptor (IGF-1R) monoclonal antibodies (mAbs) were developed for clinical use in treating advanced stage cancers. We postulated that IGF-1R mAbs could represent a viable therapeutic tool to target IGF-1 action, and potentially mimic the beneficial effects associated with diminished IGF-1 signaling observed in animal models. In order to test this possibility, we engineered a murinized version of the anti-IGF-1R mAb, L2-C (L2-Cmu), in order to reduce effector function and enable chronic administration in mice. L2-Cmu proved feasible and well tolerated in older animals, and consistent with genetic models of IGF-1R heterozygosity, improves female healthspan and increases median lifespan by 9%. Importantly, these effects were achieved even though treatment was not initiated until 18 months of age. Thus, these data suggest that late-life targeting of IGF-1R signaling can recapitulate effects observed in genetic models of constitutive IGF-1R haploinsufficiency on lifespan. As IGF-1R mAbs are readily available for human use, these observations warrant further study into potentially harnessing these drugs to target at least some manifestations of aging.