Biochemical and Functional Characterization of the Klotho-VS Polymorphism Implicated in Aging and Disease Risk

Zhou, Tracey B. Tucker; King, Gwendalyn D.; Chen, Ci Di; Abraham, Carmela R.

doi:10.1074/jbc.m113.490052

Cited by 33 publications

(28 citation statements)

References 63 publications

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“…Furthermore, elevating klotho levels in another species, mice, also enhanced cognition. Nonetheless, it is important to note that the KL-VS variant may also exert other effects such as altering klotho activities (Abraham et al, 2012; Arking et al, 2002; Tucker Zhou et al, 2013). Additional studies are needed to further explore the pleiotropic functions of this lifespan-extending and cognition-enhancing factor.…”

Section: Discussionmentioning

confidence: 99%

“…Higher klotho levels increase lifespan in mice (Kurosu et al, 2005) and nematodes (Chateau et al, 2010). In humans, a single allele of the KL-VS variant of the KLOTHO gene, which increases secreted klotho (Arking et al, 2002) and more strongly activates FGF23 signaling (Tucker Zhou et al, 2013) in cell culture, promotes longevity (Arking et al, 2005; Arking et al, 2002; Invidia et al, 2010) and diminishes age-related heart disease (Arking et al, 2005). …”

Section: Introductionmentioning

confidence: 99%

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Life Extension Factor Klotho Enhances Cognition

et al. 2014

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Summary Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a life span-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an NMDA receptor subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition at different life stages and counteract cognitive decline.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Life Extension Factor Klotho Enhances Cognition

et al. 2014

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“…7 A ). sKlotho is reported to form dimers (6) and KL2 domain may play a role in dimer formation, enhancing the in vivo function of KL1. Future studies will address the role of the KL2 domain in the binding and regulation of raft‐dependent function.…”

Section: Discussionmentioning

confidence: 99%

Modeled structural basis for the recognition of α2–3‐sialyllactose by soluble Klotho

Wright

Xie

et al. 2017

FASEB j.

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Soluble Klotho (sKlotho) is the shed ectodomain of antiaging membrane Klotho that contains 2 extracellular domains KL1 and KL2, each of which shares sequence homology to glycosyl hydrolases. sKlotho elicits pleiotropic cellular responses with a poorly understood mechanism of action. Notably, in injury settings, sKlotho confers cardiac and renal protection by down-regulating calcium-permeable transient receptor potential canonical type isoform 6 (TRPC6) channels in cardiomyocytes and glomerular podocytes. Inhibition of PI3K-dependent exocytosis of TRPC6 is thought to be the underlying mechanism, and recent studies showed that sKlotho interacts with α2-3-sialyllactose-containing gangliosides enriched in lipid rafts to inhibit raft-dependent PI3K signaling. However, the structural basis for binding and recognition of α2-3-sialyllactose by sKlotho is unknown. Using homology modeling followed by docking, we identified key protein residues in the KL1 domain that are likely involved in binding sialyllactose. Functional experiments based on the ability of Klotho to down-regulate TRPC6 channel activity confirm the importance of these residues. Furthermore, KL1 domain binds α2-3-sialyllactose, down-regulates TRPC6 channels, and exerts protection against stress-induced cardiac hypertrophy in mice. Our results support the notion that sialogangliosides and lipid rafts are membrane receptors for sKlotho and that the KL1 domain is sufficient for the tested biologic activities. These findings can help guide the design of a simpler Klotho mimetic.-Wright, J. D., An, S.-W., Xie, J., Yoon, J., Nischan, N., Kohler, J. J., Oliver, N., Lim, C., Huang, C.-L. Modeled structural basis for the recognition of α2-3-sialyllactose by soluble Klotho.

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“…The longevity gene Klotho was identified in mice as an aging suppressor . Two variants in the human KLOTHO gene ( KL ), rs9536314 (F352V), and rs9527025 (C370S) segregate together and form a haplotype (KL‐VS) that increases klotho secretion and may alter its functions . Klotho circulates throughout the body and brain .…”

Section: Introductionmentioning

confidence: 99%

Variation in longevity gene KLOTHO is associated with greater cortical volumes

Yokoyama

Sturm

Bonham

et al. 2015

Ann Clin Transl Neurol

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ObjectiveIdentifying genetic variation associated with brain structures in aging may elucidate new biologic mechanisms underlying resilience to cognitive decline. We investigated whether carrying one copy of the protective haplotype “KL-VS” in longevity gene KLOTHO (KL) is associated with greater gray matter volume in healthy human aging compared to carrying no copies.MethodsWe performed unbiased whole-brain analysis in cognitively normal older adults from two independent cohorts to assess the relationship between KL-VS and gray matter volume using voxel-based morphometry.ResultsWe found that KL-VS heterozygosity was associated with greater volume in right dorsolateral prefrontal cortex (rDLPFC). Because rDLPFC is important for executive function, we analyzed working memory and processing speed in individuals. KL-VS heterozygosity was associated with enhanced executive function. Larger rDLPFC volume correlated with better executive function across the lifespan examined. Statistical analysis suggested that volume partially mediates the effect of genotype on cognition.InterpretationThese results suggest that variation in KL is associated with bigger brain volume and better function.

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Biochemical and Functional Characterization of the Klotho-VS Polymorphism Implicated in Aging and Disease Risk

Cited by 33 publications

References 63 publications

Life Extension Factor Klotho Enhances Cognition

Life Extension Factor Klotho Enhances Cognition

Modeled structural basis for the recognition of α2–3‐sialyllactose by soluble Klotho

Variation in longevity gene KLOTHO is associated with greater cortical volumes

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