The Klotho gene, when overexpressed in mice, extends lifespan and suppresses aging. Klotho is a circulating hormone that binds to a cell-surface receptor and inhibits intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending lifespan. Klotho-deficient mice exhibit multiple age-related disorders, including ectopic calcification, skin atrophy, muscle atrophy, osteoporosis, arteriosclerosis, and pulmonary emphysema, and suffer premature death. The Klotho protein may function as an anti-aging hormone in mammals by regulating age-related disorders or natural aging processes. Klotho is a single-pass transmembrane protein detectable in limited tissues, particularly the distal convoluted tubules in the kidney and the choroid plexus in the brain. The extracellular domain of Klotho is composed of two internal repeats, KL1 and KL2, which share amino acid sequence homology with β-glucosidases of bacteria and plants. However, glucosidase activity is not present in recombinant Klotho protein. Klotho overexpression extends lifespan in mice, with transgenic lines showing a 20-30% increase in lifespan compared to wild-type controls. Klotho overexpression also increases resistance to insulin and IGF1, as evidenced by reduced glucose infusion rates and attenuated hypoglycemic responses to injected insulin and IGF1 in male transgenic mice. Klotho functions as a hormone, with its extracellular domain detectable in the blood and cerebrospinal fluid. Recombinant Klotho extracellular peptide injected into mice attenuates the hypoglycemic response expected from insulin alone and rapidly increases blood glucose levels. Klotho peptide inhibits insulin action directly in peripheral tissues by disrupting one or more alternative insulin-dependent intracellular signaling pathways. Klotho inhibits intracellular insulin and IGF1 signaling, reducing tyrosine phosphorylation of insulin and IGF1 receptors, which results in reduced activity of IRS proteins and their association with PI3-kinase, thereby inhibiting insulin and IGF1 signaling. Inhibition of insulin and IGF1 signaling rescues KL⁻/⁻ phenotypes, as evidenced by improved survival and amelioration of age-related pathologies in KL⁻/⁻ mice heterozygous for an IRS-1 null allele. These findings suggest that Klotho functions as an aging suppressor gene in mammals, modulating aging through mechanisms independent of food intake and growth. Klotho appears to be a peptide hormone that modulates such signaling and thereby mediates insulin metabolism and aging.The Klotho gene, when overexpressed in mice, extends lifespan and suppresses aging. Klotho is a circulating hormone that binds to a cell-surface receptor and inhibits intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending lifespan. Klotho-deficient mice exhibit multiple age-related disorders, including ectopic calcification, skin atrophy, muscle atrophy, osteoporosis, arteriosclerosis, and pulmonary emphysema, and suffer premature death. The Klotho protein may function as an anti-aging hormone in mammals by regulating age-related disorders or natural aging processes. Klotho is a single-pass transmembrane protein detectable in limited tissues, particularly the distal convoluted tubules in the kidney and the choroid plexus in the brain. The extracellular domain of Klotho is composed of two internal repeats, KL1 and KL2, which share amino acid sequence homology with β-glucosidases of bacteria and plants. However, glucosidase activity is not present in recombinant Klotho protein. Klotho overexpression extends lifespan in mice, with transgenic lines showing a 20-30% increase in lifespan compared to wild-type controls. Klotho overexpression also increases resistance to insulin and IGF1, as evidenced by reduced glucose infusion rates and attenuated hypoglycemic responses to injected insulin and IGF1 in male transgenic mice. Klotho functions as a hormone, with its extracellular domain detectable in the blood and cerebrospinal fluid. Recombinant Klotho extracellular peptide injected into mice attenuates the hypoglycemic response expected from insulin alone and rapidly increases blood glucose levels. Klotho peptide inhibits insulin action directly in peripheral tissues by disrupting one or more alternative insulin-dependent intracellular signaling pathways. Klotho inhibits intracellular insulin and IGF1 signaling, reducing tyrosine phosphorylation of insulin and IGF1 receptors, which results in reduced activity of IRS proteins and their association with PI3-kinase, thereby inhibiting insulin and IGF1 signaling. Inhibition of insulin and IGF1 signaling rescues KL⁻/⁻ phenotypes, as evidenced by improved survival and amelioration of age-related pathologies in KL⁻/⁻ mice heterozygous for an IRS-1 null allele. These findings suggest that Klotho functions as an aging suppressor gene in mammals, modulating aging through mechanisms independent of food intake and growth. Klotho appears to be a peptide hormone that modulates such signaling and thereby mediates insulin metabolism and aging.