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Cell Rep. 2014 May 22;7(4):1065-76. doi: 10.1016/j.celrep.2014.03.076. Epub 2014 May 10.

Life extension factor klotho enhances cognition.

Author information

1
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: dena.dubal@ucsf.edu.
2
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
4
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
5
Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90024, USA.
6
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
7
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
8
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
9
Program in Translational NeuroPsychiatric Genomics, Institute for Neurosciences, Departments of Neurology & Psychiatry, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
10
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
11
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: lmucke@gladstone.ucsf.edu.

Abstract

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 lifespan-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 N-methyl-D-aspartate receptor (NMDAR) 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 and counteract cognitive deficits at different life stages.

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PMID:
24813892
PMCID:
PMC4176932
DOI:
10.1016/j.celrep.2014.03.076
[Indexed for MEDLINE]
Free PMC Article

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