A defect in Klotho gene expression in mice accelerates the degeneration of multiple age-sensitive traits. Here, we show that overexpression of Klotho in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in Klotho-deficient mice was observed by perturbing insulin and IGF1 signaling, suggesting that Klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. Klotho protein may function as an anti-aging hormone in mammals.Klotho was originally identified as a mutated gene in a mouse strain that accelerates agedependent loss of function in multiple age-sensitive traits (1). An insertional mutation that disrupts the 5′ promoter region of the Klotho gene resulted in a strong hypomorphic allele. Mice homozygous for the mutated allele (KL −/− mice) appeared normal until 3 to 4 weeks old but then began to manifest multiple age-related disorders observed in humans, including ectopic calcification, skin atrophy, muscle atrophy, osteoporosis, arteriosclerosis, and pulmonary emphysema. KL −/− mice suffered premature death around two months of age.

klotho is an aging suppressor gene and extends life span when overexpressed in mice. Klotho protein was recently demonstrated to function as a hormone that inhibits insulin/insulin-like growth factor-1 (IGF-1) signaling. Here we show that Klotho protein increases resistance to oxidative stress at the cellular and organismal level in mammals. Klotho protein activates the FoxO forkhead transcription factors that are negatively regulated by insulin/IGF-1 signaling, thereby inducing expression of manganese superoxide dismutase. This in turn facilitates removal of reactive oxygen species and confers oxidative stress resistance. Thus, Klotho-induced inhibition of insulin/IGF-1 signaling is associated with increased resistance to oxidative stress, which potentially contributes to the anti-aging properties of klotho.A defect in klotho gene expression in mice leads to a syndrome closely resembling human aging, including shortened life span, infertility, growth arrest, hypoactivity, skin atrophy, premature thymic involution, arteriosclerosis, osteoporosis, and pulmonary emphysema (1). Conversely, overexpression of the klotho gene extends the life span in the mouse (2), indicating that the klotho gene functions as an aging suppressor gene in mammals that delays aging when overexpressed and accelerates the development of aging-like disorders when disrupted. The klotho gene encodes a single-pass transmembrane protein and is expressed only in limited tissues, notably the distal convoluted tubules in the kidney and the choroid plexus in the brain (1). The extracellular domain of Klotho protein is shed and secreted into the blood. It then binds to a high affinity but as yet unidentified cell-surface Klotho receptor and signals suppression of tyrosine phosphorylation of insulin/ IGF-1 2 receptors and insulin receptor substrates (IRS), association of IRS with phosphatidylinositol 3-kinase (PI3K), and serine phosphorylation of Akt/PKB (2). Thus, Klotho protein is a hormone that inhibits the intracellular insulin/IGF-1 signaling cascade. This activity likely contributes to the suppression of aging by Klotho, because inhibition of insulin-like signaling is an evolutionarily conserved mechanism for extending life span (see Ref. 3 for review). Indeed, we observed alleviation of aging-like phenotypes in Klotho deficient mice (KL Ϫ/Ϫ mice) by genetic perturbation of insulin/IGF-1 signaling, indicating that the activity of Klotho that inhibits insulin/IGF-1 signaling accounts for its anti-aging properties, at least in part (2). It remains to be determined whether or not the inhibitory effect of Klotho protein on IRS, PI3K, and Akt is entirely dependent on its ability to inhibit insulin/IGF-1 receptors. Notably, single nucleotide polymorphisms in the human KLOTHO gene are associated with longevity (4) and common age-related diseases including coronary artery disease (5), osteoporosis (6 -8), and stroke (9), strongly arguing that Klotho regulates aging in humans. Increased resistance to oxidative stress is associated with increased longevi...