igf-1 damaging the gene encoding insulin igf-1 receptor extend the lifespan of flies & mice experiment by Cynthia Kenyon, PhD . Centenarian carry mutation that reduce activity of igf-1 receptors .Genetic mutation that reduce the activity of the IGF-1 (Insulin-like Growth Factor-1) pathway are among the most consistently linked factors to extended lifespan across species, from yeast & worms to humans.  Human Genetic Evidence in humans, "mutated" IGF-1 usually refer to rare loss-of-function variants that slightly dampen the signal rather than stopping it entirely. IGF-1 Receptor (IGF1R) Mutation: Centenarian studies (particularly in Ashkenazi Jewish cohorts) have found an overrepresentation of heterozygous mutation in the IGF1R gene. These individuals often have higher serum IGF-1 levels because their bodies are trying to compensate for "resistant" receptors that don't signal efficiently. Reduced Stature and Longevity: These mutations have been linked to shorter height in the female offspring of centenarians, consistent with reduced growth signaling, similar to findings in long-lived dwarf mice. Rare IGF-1 Gene Variants: A 2025 study identified two extremely rare coding mutation in the IGF-1 hormone gene itself—Ile91Leu and Ala118Thr—linked to exceptional longevity. Ile91Leu weaken the hormone's physical binding to its receptor. Ala118Thr significantly lower the amount of circulating IGF-1. Laron Syndrome: This rare condition involve a mutation in the Growth Hormone Receptor (GHR), leading to nearly undetectable IGF-1 level. While these individuals are characterized by dwarfism, they are remarkably resistant to cancer & diabetes, though their overall lifespan extension compared to relatives is still debated. Why Lower IGF-1 Extends Life Reduced IGF-1 signaling acts as a "metabolic switch" that shifts the cell's priority from growth to maintenance: FOXO Activation: Lower IGF-1 allows FOXO3 transcription factors to enter the nucleus, where they trigger the production of antioxidants and DNA repair enzymes. Autophagy & Proteostasis: It enhance autophagy (cellular "self-cleaning"), which help clear out the misfolded protein and glycation damage you asked about earlier. Stress Resistance: Cells with lower IGF-1 signaling are significantly more resistant to heat and oxidative stress. Slower Proliferation: By dampening cell cycle progression, it reduces the accumulation of senescent "zombie" cells and the risk of malignant tumors. Summary of Longevity Effects Species Typical Lifespan Increase Notable Feature C. elegans Up to 100%+ First model to prove the IIS-longevity link. Mice 16–55% Often shows stronger effects in females. Dogs Varies by breed Small dogs (with lower IGF-1) outlive large dogs. Humans Significant (Centenarians) Linked to "healthy aging" and disease resistance may the Holy Roman Catholic Church be blessed by God the Father God the Son & God the Holy Spirit Hallelujah Hallelujah Blessed be the word of the Lord for Christ is risen Hallelujah Hallelujah peace be still in Nomine Patris et FiLii et Spiritus Sancti amen