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Suppression of aging in mice by the hormone Klotho.

ABSTRACT: 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.

SUBMITTER: Kurosu H

PROVIDER: S-EPMC2536606 | biostudies-literature | 2005 Sep

REPOSITORIES: biostudies-literature

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Suppression of aging in mice by the hormone Klotho.

Kurosu Hiroshi H Yamamoto Masaya M Clark Jeremy D JD Pastor Johanne V JV Nandi Animesh A Gurnani Prem P McGuinness Owen P OP Chikuda Hirotaka H Yamaguchi Masayuki M Kawaguchi Hiroshi H Shimomura Iichiro I Takayama Yoshiharu Y Herz Joachim J Kahn C Ronald CR Rosenblatt Kevin P KP Kuro-o Makoto M

Science (New York, N.Y.) 20050825 5742

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 pertur ...[more]

PMID: 16123266

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Sox4 links tumor suppression to accelerated aging in mice

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Molecular basis of Klotho: from gene to function in aging.

Project description:The discovery of the Klotho (KL) gene, which was originally identified as a putative aging-suppressor gene, has generated tremendous interest and has advanced understanding of the aging process. In mice, the overexpression of the KL gene extends the life span, whereas mutations to the KL gene shorten the life span. The human KL gene encodes the α-Klotho protein, which is a multifunctional protein that regulates the metabolism of phosphate, calcium, and vitamin D. α-Klotho also may function as a hormone, although the α-Klotho receptor(s) has not been found. Point mutations of the KL gene in humans are associated with hypertension and kidney disease, which suggests that α-Klotho may be essential to the maintenance of normal renal function. Three α-Klotho protein types with potentially different functions have been identified: a full-length transmembrane α-Klotho, a truncated soluble α-Klotho, and a secreted α-Klotho. Recent evidence suggests that α-Klotho suppresses the insulin and Wnt signaling pathways, inhibits oxidative stress, and regulates phosphatase and calcium absorption. In this review, we provide an update on recent advances in the understanding of the molecular, genetic, biochemical, and physiological properties of the KL gene. Specifically, this review focuses on the structure of the KL gene and the factors that regulate KL gene transcription, the key sites in the regulation of α-Klotho enzyme activity, the α-Klotho signaling pathways, and the molecular mechanisms that underlie α-Klotho function. This current understanding of the molecular biology of the α-Klotho protein may offer new insights into its function and role in aging.

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Klotho Deficiency Accelerates Stem Cells Aging by Impairing Telomerase Activity.

Project description:Understanding the effect of molecular pathways involved in the age-dependent deterioration of stem cell function is critical for developing new therapies. The overexpression of Klotho (KL), an antiaging protein, causes treated animal models to enjoy extended life spans. Now, the question stands: Does KL deficiency accelerate stem cell aging and telomere shortening? If so, what are the specific mechanisms by which it does this, and is cycloastragenol (CAG) treatment enough to restore telomerase activity in aged stem cells? We found that KL deficiency diminished telomerase activity by altering the expression of TERF1 and TERT, causing impaired differentiation potential, pluripotency, cellular senescence, and apoptosis in stem cells. Telomerase activity decreased with KL-siRNA knockdown. This suggests that both KL and telomeres regulate the stem cell aging process through telomerase subunits TERF1, POT1, and TERT using the TGFβ, Insulin, and Wnt signaling. These pathways can rejuvenate stem cell populations in a CD90-dependent mechanism. Stem cell dysfunctions were largely provoked by KL deficiency and telomere shortening, owing to altered expression of TERF1, TGFβ1, CD90, POT1, TERT, and basic fibroblast growth factor (bFGF). The CAG treatment partially rescued telomerase deterioration, suggesting that KL plays a critical role in life-extension by regulating telomere length and telomerase activity.

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