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.
authors.affiliation: 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.
authors.forename: Dena B
authors.initials: DB
authors.lastname: Dubal
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yokoyama
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Broestl
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Kurtresha
authors.initials: K
authors.lastname: Worden
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Virginia E
authors.initials: VE
authors.lastname: Sturm
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kim
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90024, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Klein
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
authors.forename: Gui-Qiu
authors.initials: GQ
authors.lastname: Yu
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Ho
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
authors.forename: Kirsten E
authors.initials: KE
authors.lastname: Eilertson
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-o
authors.affiliation: 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.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90024, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90024, USA.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Small
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Joel H
authors.initials: JH
authors.lastname: Kramer
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Carmela R
authors.initials: CR
authors.lastname: Abraham
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: 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.
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D003071:Cognition / Q000502:physiology*; D015331:Cohort Studies; D005260:Female; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D000090265:Klotho Proteins; D008017:Life Expectancy; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
chemical_list: C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D005966:Glucuronidase; D000090265:Klotho Proteins