Life Extension Factor Klotho Enhances Cognition

Dena B. Dubal, Jennifer S. Yokoyama, Lei Zhu, Lauren Broestl, Kurtresha Worden, Dan Wang, Virginia E. Sturm, Daniel Kim, Eric Klein, Gui Qiu Yu, Kaitlyn Ho, Kirsten E. Eilertson, Lei Yu, Makoto Kuro-o, Philip L. De Jager, Giovanni Coppola, Gary W. Small, David A. Bennett, Joel H. Kramer, Carmela R. AbrahamBruce L. Miller, Lennart Mucke

Research output: Contribution to journalArticle

109 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1065-1076
Number of pages12
JournalCell Reports
Volume7
Issue number4
DOIs
StatePublished - May 22 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Dubal, D. B., Yokoyama, J. S., Zhu, L., Broestl, L., Worden, K., Wang, D., Sturm, V. E., Kim, D., Klein, E., Yu, G. Q., Ho, K., Eilertson, K. E., Yu, L., Kuro-o, M., De Jager, P. L., Coppola, G., Small, G. W., Bennett, D. A., Kramer, J. H., ... Mucke, L. (2014). Life Extension Factor Klotho Enhances Cognition. Cell Reports, 7(4), 1065-1076. https://doi.org/10.1016/j.celrep.2014.03.076