Small-molecule IGF1R inhibitors extend healthspan in a mouse model

Antagonistic pleiotropy of the IGF-1 signaling cascade is well recognized, as it promotes growth and development at younger ages and delays aging later in life. The goal of this study is to test in a mouse longevity experiment whether orally delivered small-molecule IGF1R inhibitors have promise as an anti-aging therapy. C57BL/6 mice (25 male and 25 female mice per treatment) were treated with selective IGF1R inhibitors, picropodophyllin (PPP) or 5-[3-(phenylmethoxy)phenyl]-7-[trans-3-(1-pyrrolidinylmethyl)cyclobutyl]-7H-pyrrolo[3-d]pyrimidin-4-amine (NVP-ADW742), via powdered diets starting at 13 months of age, and physiological and behavioral parameters, as well as survival, were assessed. Both compounds protected both sexes from short-term memory decline; reduced systolic blood pressure in males and pulse rate in both sexes; rescued declining glucose tolerance in males; and abolished grey hair development, reduced frailty, and protected against decline in grip strength in female mice. There were no sex differences in survival curves within groups. No significant differences between groups were observed in the Kaplan-Meier analysis. However, the survival curve in the NVP-ADW742 group was "squarer" than in controls, indicating a 93-day longer healthspan (p = 0.02). PPP treatment was associated with toxicity (GI bleeding). Additional analysis of the drug likeness of NVP-ADW742 demonstrated potential cardiotoxicity and brain bioaccumulation. To conclude, small-molecule IGF1R inhibitors hold promise as a therapy that may improve human health span and lifespan; however, both molecules tested in this study have side effects that may outweigh their anti-aging effects. Statements and DeclarationsYB is an employee of ReGENE LLC. GB received compensation from ReGENE LLC as a consultant. CJE received compensation from and is a member of ReGENE LLC. AS received compensation from and is a member of ReGENE LLC. TS declares no conflict of interest.