PMID- 24813892 OWN - NLM STAT- MEDLINE DCOM- 20150420 LR - 20211203 IS - 2211-1247 (Electronic) VI - 7 IP - 4 DP - 2014 May 22 TI - Life extension factor klotho enhances cognition. PG - 1065-76 LID - S2211-1247(14)00287-3 [pii] LID - 10.1016/j.celrep.2014.03.076 [doi] AB - 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. CI - Copyright (c) 2014 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Dubal, Dena B AU - Dubal DB AD - 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. FAU - Yokoyama, Jennifer S AU - Yokoyama JS AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Zhu, Lei AU - Zhu L AD - Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Broestl, Lauren AU - Broestl L AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Worden, Kurtresha AU - Worden K AD - Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Wang, Dan AU - Wang D AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Sturm, Virginia E AU - Sturm VE AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Kim, Daniel AU - Kim D AD - Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA. FAU - Klein, Eric AU - Klein E AD - Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90024, USA. FAU - Yu, Gui-Qiu AU - Yu GQ AD - Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA. FAU - Ho, Kaitlyn AU - Ho K AD - Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA. FAU - Eilertson, Kirsten E AU - Eilertson KE AD - Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. FAU - Yu, Lei AU - Yu L AD - Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA. FAU - Kuro-o, Makoto AU - Kuro-o M AD - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan. FAU - De Jager, Philip L AU - De Jager PL AD - 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. FAU - Coppola, Giovanni AU - Coppola G AD - Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90024, USA. FAU - Small, Gary W AU - Small GW AD - Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90024, USA. FAU - Bennett, David A AU - Bennett DA AD - Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA. FAU - Kramer, Joel H AU - Kramer JH AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Abraham, Carmela R AU - Abraham CR AD - Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Miller, Bruce L AU - Miller BL AD - Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. FAU - Mucke, Lennart AU - Mucke L AD - 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. LA - eng GR - P50 AG023501/AG/NIA NIH HHS/United States GR - AG17917/AG/NIA NIH HHS/United States GR - R01 AG019712/AG/NIA NIH HHS/United States GR - R01 AG017917/AG/NIA NIH HHS/United States GR - AG00001/AG/NIA NIH HHS/United States GR - NS065780/NS/NINDS NIH HHS/United States GR - AG19724/AG/NIA NIH HHS/United States GR - R01 AG015819/AG/NIA NIH HHS/United States GR - P01 AG025831/AG/NIA NIH HHS/United States GR - AG025831/AG/NIA NIH HHS/United States GR - RR00865/RR/NCRR NIH HHS/United States GR - K23 AG040127/AG/NIA NIH HHS/United States GR - AG032289/AG/NIA NIH HHS/United States GR - RF1 AG015819/AG/NIA NIH HHS/United States GR - AG010435/AG/NIA NIH HHS/United States GR - M01 RR000865/RR/NCRR NIH HHS/United States GR - AG034531/AG/NIA NIH HHS/United States GR - P50AG23501/AG/NIA NIH HHS/United States GR - P30 NS065780/NS/NINDS NIH HHS/United States GR - P01 AG000001/AG/NIA NIH HHS/United States GR - P01 AG019724/AG/NIA NIH HHS/United States GR - AG15819/AG/NIA NIH HHS/United States GR - P30 AG010161/AG/NIA NIH HHS/United States GR - R01 AG018440/AG/NIA NIH HHS/United States GR - R37 AG018440/AG/NIA NIH HHS/United States GR - P01 AG010435/AG/NIA NIH HHS/United States GR - AG022074/AG/NIA NIH HHS/United States GR - AG019712/AG/NIA NIH HHS/United States GR - P01 AG022074/AG/NIA NIH HHS/United States GR - AG18440/AG/NIA NIH HHS/United States GR - R01 AG032289/AG/NIA NIH HHS/United States GR - K08 AG034531/AG/NIA NIH HHS/United States GR - RR18938-01/RR/NCRR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140510 PL - United States TA - Cell Rep JT - Cell reports JID - 101573691 RN - 0 (NR2B NMDA receptor) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - EC 3.2.1.31 (Glucuronidase) RN - EC 3.2.1.31 (Klotho Proteins) SB - IM CIN - Nat Rev Neurosci. 2014 Jul;15(7):425. PMID: 24938722 MH - Age Factors MH - Aged MH - Aged, 80 and over MH - Animals MH - Cognition/*physiology MH - Cohort Studies MH - Female MH - Glucuronidase/genetics/metabolism/*physiology MH - Humans MH - Klotho Proteins MH - Life Expectancy MH - Male MH - Memory/physiology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Middle Aged MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Synapses/metabolism PMC - PMC4176932 MID - NIHMS586250 EDAT- 2014/05/13 06:00 MHDA- 2015/04/22 06:00 PMCR- 2014/09/27 CRDT- 2014/05/13 06:00 PHST- 2013/04/05 00:00 [received] PHST- 2014/01/10 00:00 [revised] PHST- 2014/03/31 00:00 [accepted] PHST- 2014/05/13 06:00 [entrez] PHST- 2014/05/13 06:00 [pubmed] PHST- 2015/04/22 06:00 [medline] PHST- 2014/09/27 00:00 [pmc-release] AID - S2211-1247(14)00287-3 [pii] AID - 10.1016/j.celrep.2014.03.076 [doi] PST - ppublish SO - Cell Rep. 2014 May 22;7(4):1065-76. doi: 10.1016/j.celrep.2014.03.076. Epub 2014 May 10.