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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.
Biorxiv : the Preprint Server for Biology
|April 27, 2026
Summary
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.
