Researchers from the Gladstone Institutes and the University of California-San Francisco have discovered that a common form of a gene already associated with long life also improves learning and memory. They believe their finding could have implications for treating age-related diseases like Alzheimer's.
The scientists found that people who carry a single copy of the KL-VS variant of the klotho gene perform better on a wide variety of cognitive tests. When the researchers modeled the effects in mice, they found it strengthened the connections between neurons that make learning possible by increasing the action of a cell receptor critical to forming memories.
Researchers have long suspected that some people may be protected from Alzheimer’s because of their greater cognitive capacity. Since elevated levels of the klotho protein appear to improve cognition throughout the lifespan, raising klotho levels could build cognitive reserve as a bulwark against the disease.
“As the world's population ages, cognitive frailty is our biggest biomedical challenge,” said Dena Dubal, M.D., Ph.D., assistant professor of neurology, the David A. Coulter Endowed Chair in Aging and Neurodegeneration at UCSF and lead author of the study (“Life Extension Factor Klotho Enhances Cognition”), which is published Cell Reports. “If we can understand how to enhance brain function, it would have a huge impact on people's lives.”
Klotho was discovered in 1997 and named after the Fate from Greek mythology who spins the thread of life. The investigators found that people who carry a single copy of the KL-VS variant of the Klotho gene, roughly 20% of the population, have more klotho protein in their blood than non-carriers. Besides increasing the secretion of klotho, the KL-VS variant may also change the action of the protein and is known to lessen age-related cardiovascular disease and promote longevity.
The team's report is the first to link the KL-VS variant, or allele, to better cognition in humans, and buttresses these findings with genetic, electrophysiological, biochemical and behavioral experiments in mice.
“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,” wrote the investigators. “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.”
“These surprising results pave a promising new avenue of research,” said Roderick Corriveau, Ph.D., program director at NIH's National Institute of Neurological Disorders and Stroke. “Although preliminary, they suggest klotho could be used to bump up cognition for people suffering from dementia.”
The researchers also tested the associations between the allele and age-related human cognition in three separate studies involving more than 700 people without dementia between the ages of 52 and 85. Altogether, it took about three years to conduct the work. Having the KL-VS allele did not seem to protect people from age-related cognitive decline. But overall the effect was to boost cognition, so that the middle-aged study participants began their decline from a higher point.
“Based on what was known about klotho, we expected it to affect the brain by changing the aging process,” said senior author Lennart Mucke, M.D., who directs neurological research at the Gladstone Institutes and is a professor of neurology and the Joseph B. Martin Distinguished Professor of Neuroscience at UCSF. “But this is not what we found, which suggested to us that we were on to something new and different.”