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Small-molecule IGF1R inhibitors extend healthspan in a mouse model
Yulia Balandina1, Tom Stadnikov1, Gregory Basarab1
1ReGENE LLC, Belchertown, MA, USA.
Abstract:
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.
Insights
Small-molecule IGF1R inhibitors show potential for improving healthspan and lifespan by enhancing cognitive function and physical health in mice. However, potential toxicities necessitate further investigation before human application.
Area of Science:
- Gerontology and pharmacology
- Molecular biology and aging research
Background:
- The insulin-like growth factor 1 (IGF-1) signaling cascade exhibits antagonistic pleiotropy, promoting growth and development while delaying aging.
- Small-molecule inhibitors targeting the IGF-1 receptor (IGF1R) are being explored as potential anti-aging therapies.
Purpose of the Study:
- To evaluate the efficacy of orally delivered IGF1R inhibitors, picropodophyllin (PPP) and NVP-ADW742, in a mouse longevity experiment.
- To assess the impact of these inhibitors on physiological, behavioral, and survival parameters in aging mice.
Main Methods:
- C57BL/6 mice (25 male, 25 female per group) were administered PPP or NVP-ADW742 via powdered diets starting at 13 months of age.
- Comprehensive assessment of physiological (blood pressure, glucose tolerance, heart rate), behavioral (memory, grip strength), and survival metrics.
- Analysis included Kaplan-Meier survival curves and drug likeness profiling.
Main Results:
- Both IGF1R inhibitors improved short-term memory, reduced pulse rate, and mitigated age-related declines in glucose tolerance (males) and grip strength (females).
- NVP-ADW742 treatment resulted in a "squarer" survival curve, indicating a significant healthspan extension of 93 days (p = 0.02).
- PPP treatment was linked to gastrointestinal bleeding, while NVP-ADW742 showed potential cardiotoxicity and brain bioaccumulation.
Conclusions:
- Small-molecule IGF1R inhibitors demonstrate promise for enhancing healthspan and potentially lifespan, with notable benefits in physiological and cognitive functions.
- Despite promising results, the observed toxicities (GI bleeding with PPP, potential cardiotoxicity/brain accumulation with NVP-ADW742) require careful consideration and may limit therapeutic application.
- Further research is warranted to develop safer IGF1R inhibitors with a more favorable benefit-risk profile for anti-aging interventions.
