Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
Jennifer S. Yokoyama
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
Lei Zhu
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
Lauren Broestl
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
Kurtresha Worden
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
Dan Wang
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
Virginia E. Sturm
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
Daniel Kim
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
Eric Klein
Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90024, USA
Gui-Qiu Yu
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
Kaitlyn Ho
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
Kirsten E. Eilertson
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA
Lei Yu
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA
Makoto Kuro-o
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Philip L. De Jager
Program in Translational NeuroPsychiatric Genomics, Institute for Neurosciences, Departments of Neurology & Psychiatry, Brigham and Women’s Hospital, Boston, MA 02115, USA
Giovanni Coppola
Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90024, USA
Gary W. Small
Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90024, USA
David A. Bennett
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA
Joel H. Kramer
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
Carmela R. Abraham
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA
Bruce L. Miller
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
Lennart Mucke
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
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.
