Aging is linked to the activity of the IGF-1 signaling pathway, which promotes growth in the young but accelerates wear and tear in the old. This is an example of antagonistic pleiotropy: the same mechanism is beneficial at one age and harmful at another. Suppressing IGF1R extended lifespan in various animals, but human data are contradictory. It is therefore important to test whether this pathway can be safely slowed in adults using low-molecular-weight drugs that can be taken by mouth.
In a pilot experiment on 55 male mice, the minimal doses producing a systemic response were determined: 1 mg/kg for PPP and 0.5 mg/kg for NVP-ADW742. In the main experiment, 150 mice (75 males and 75 females) at 55 weeks of age were randomly divided into three groups: control, PPP, and NVP-ADW742. The drugs were added to powdered chow. The mice were followed until 151 weeks of age, with regular measurements of memory, grip strength, coordination, blood pressure, glucose levels, coat graying, and overall frailty. Mortality was analyzed by the Kaplan-Meier method.
Both inhibitors protected the mice from age-related decline in short-term memory: in control animals memory dropped significantly, while in treated animals it remained at the level of young mice. In males, systolic pressure and heart rate decreased, and glucose tolerance improved. In females, coat graying decreased (from 2.9% to 0.6-0.9% gray hair) and the frailty index fell threefold. NVP-ADW742 increased healthspan by 93 days (p=0.02), although total lifespan did not change significantly. PPP produced no such effect and even caused more cases of gastrointestinal bleeding, probably because of a toxic breakdown product.
The work confirms that suppressing IGF1R in later life can improve health without serious side effects, provided the drug is sufficiently pure. This supports the idea of antagonistic pleiotropy and points to IGF1R as a promising target for geroprotectors. However, both compounds tested are unsuitable for the clinic: PPP is unstable and toxic, while NVP-ADW742 is poorly absorbed, rapidly cleared, and affects the cardiac hERG channel.
New small molecules are needed that selectively block IGF1R but lack these drawbacks: they must be stable, bioavailable, not accumulate in the brain, and not disturb heart rhythm. Prodrugs or analogs with improved pharmacokinetics could be developed. It is also important to understand which tissues and signaling pathways are responsible for the geroprotective effect, so that it can be targeted precisely.
The results may influence the development of anti-aging therapy and research into metabolic and cardiovascular diseases linked to aging.
Synthesize and test new IGF1R inhibitors with better drug-like properties. Test them in larger groups of mice and in other models of aging.
Gerontology still faces the unresolved question of how to separate the beneficial effects of IGF-1 in youth from the harmful ones in old age. This work shows that late intervention can be safe, but it requires precise dosing and drug purity. It is also unclear why the effects differ between males and females, which reflects the broader problem of sexual dimorphism in aging.
In female mice receiving IGF1R inhibitors, the coat remained black and glossy until death, whereas control animals turned gray. This brings to mind the folk observation that stress and growth hormones accelerate graying.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.