@article{29e5b6fc1d334fd188787b1b42e4d4ee,
title = "Life Extension Factor Klotho Enhances Cognition",
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.",
author = "Dubal, {Dena B.} and Yokoyama, {Jennifer S.} and Lei Zhu and Lauren Broestl and Kurtresha Worden and Dan Wang and Sturm, {Virginia E.} and Daniel Kim and Eric Klein and Yu, {Gui Qiu} and Kaitlyn Ho and Eilertson, {Kirsten E.} and Lei Yu and Makoto Kuro-o and {De Jager}, {Philip L.} and Giovanni Coppola and Small, {Gary W.} and Bennett, {David A.} and Kramer, {Joel H.} and Abraham, {Carmela R.} and Miller, {Bruce L.} and Lennart Mucke",
note = "Funding Information: We thank X. Wang, C. Wang, and W. Guo for technical assistance; J. Palop, N. Devidze, B. Djukic, P. Taneja, A. Gazzaley, and S. Hauser for discussions; A. Karydas, G. Klein, P. Siddarth, and N. Patel for assistance accessing genetic, cognitive, or biospecimen databases; M. Dela Cruz for administrative support; and M. Kelley, A. Moreno, and T. Singh for graphics. Primary support for human data analyses and mouse studies was provided by NIH grants NS065780 and AG022074 (to L.M.) and AG034531 (to D.B.D.); gifts from the S.D. Bechtel, Jr. (to L.M.) and Coulter-Weeks (to D.B.D.) Foundations; a MetLife Foundation Award (to L.M.) and American Federation for Aging Award (to D.B.D.); and NIH RR18938-01 to the Gladstone Institutes. Additional support, including for assembly and characterization of human cohorts, was provided by NIH grants AG00001 (to C.R.A.), AG18440 and AG010435 (to E.K.), AG019712 (to M.K.), and P50AG23501 and AG19724 (to B.L.M.), Hillblom Aging Network (to B.L.M.), AG032289 (to J.H.K.), AG025831 and RR00865 (to G.W.S.), and AG15819 and AG17917 (to D.A.B.). ",
year = "2014",
month = may,
day = "22",
doi = "10.1016/j.celrep.2014.03.076",
language = "English (US)",
volume = "7",
pages = "1065--1076",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}