Pathway
Insulin / IGF-1 Signalling
Last updated Sun May 17 2026 00:00:00 GMT+0000 (Coordinated Universal Time)
What it is
The insulin / IGF-1 signalling (IIS) pathway is one of the oldest and best conserved longevity pathways. The original C. elegans daf-2 lifespan mutants doubled worm lifespan via reduced IIS. The mammalian analog spans growth hormone → IGF-1 → insulin receptor → PI3K → AKT → FOXO transcription factors.
Why it matters
- Reduced IIS → longer life across species. Heterozygous IGF-1R knockout female mice live longer.
- Laron-syndrome humans (GH-receptor deficient) show very low cancer and diabetes despite obesity.
- Centenarian cohorts (Ashkenazi) over-represent IGF-1R variants with reduced signalling.
- FOXO3 variants are among the most replicated longevity associations in human GWAS.
The trade-off
Children with low GH/IGF-1 have growth retardation; older adults with very low IGF-1 have higher frailty and mortality (J-curve). The longevity signal is for moderately reduced IIS in adulthood, not pathological loss.
What lowers it
- Caloric restriction and protein restriction.
- Methionine restriction.
- Plant-skewed diets (lower IGF-1 than animal-protein-heavy diets).
Related entries
Deregulated nutrient-sensing, FOXO transcription factors, Klotho.
References
- Junnila, R. K., List, E. O., Berryman, D. E., Murrey, J. W. & Kopchick, J. J. The GH/IGF-1 axis in ageing and longevity. Nat. Rev. Endocrinol. 9, 366–376 (2013).