The study investigates the role of the Klotho gene in aging and longevity. Klotho, originally identified in a mouse strain with age-dependent functional decline, encodes a transmembrane protein that is detectable in specific tissues. Overexpression of Klotho in mice extends their lifespan, suggesting that Klotho functions as an anti-aging hormone. The extracellular domain of Klotho protein circulates in the blood and binds to a cell-surface receptor, inhibiting insulin and IGF1 signaling. This inhibition leads to reduced activation of insulin and IGF1 receptors, decreased tyrosine phosphorylation of insulin receptor substrates, and reduced association with PI3-kinase. Klotho peptide, when injected into mice, increases blood glucose levels and reduces insulin sensitivity. Inhibiting insulin and IGF1 signaling in Klotho-deficient mice ameliorates age-related pathologies, including arteriosclerosis, ectopic calcification, skin atrophy, pulmonary emphysema, and hypogonadism. These findings suggest that Klotho-mediated inhibition of insulin and IGF1 signaling is a conserved mechanism for suppressing aging.The study investigates the role of the Klotho gene in aging and longevity. Klotho, originally identified in a mouse strain with age-dependent functional decline, encodes a transmembrane protein that is detectable in specific tissues. Overexpression of Klotho in mice extends their lifespan, suggesting that Klotho functions as an anti-aging hormone. The extracellular domain of Klotho protein circulates in the blood and binds to a cell-surface receptor, inhibiting insulin and IGF1 signaling. This inhibition leads to reduced activation of insulin and IGF1 receptors, decreased tyrosine phosphorylation of insulin receptor substrates, and reduced association with PI3-kinase. Klotho peptide, when injected into mice, increases blood glucose levels and reduces insulin sensitivity. Inhibiting insulin and IGF1 signaling in Klotho-deficient mice ameliorates age-related pathologies, including arteriosclerosis, ectopic calcification, skin atrophy, pulmonary emphysema, and hypogonadism. These findings suggest that Klotho-mediated inhibition of insulin and IGF1 signaling is a conserved mechanism for suppressing aging.