Better cognition seen with gene variant carried by one in five

May 8, 2014, University of California, San Francisco
Credit: zaldy icaonapo/Public Domain

A scientific team led by the Gladstone Institutes and UC San Francisco has discovered that a common form of a gene already associated with long life also improves learning and memory, a finding that could have implications for treating age-related diseases like Alzheimer's.

The researchers 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 , they found it strengthened the connections between neurons that make learning possible – what is known as – by increasing the action of a cell receptor critical to forming memories.

The discovery is a major step toward understanding how genes improve cognitive ability and could open a new route to treating diseases like Alzheimer's. Researchers have long suspected that some people may be protected from the disease because of their greater cognitive capacity, or reserve. 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, MD, PhD, assistant professor of neurology, the David A. Coulter Endowed Chair in Aging and Neurodegeneration at UCSF and lead author of the study, published May 8 in 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 percent 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 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. The researchers 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.

"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 (NINDS). "Although preliminary, they suggest klotho could be used to bump up cognition for people suffering from dementia."

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, MD, 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."

To get a closer look at how the gene variant operates, the researchers used mice that were engineered to produce more of the mouse version of klotho and found that these mice learned better at all stages of life. Put through mazes, these transgenic mice were more likely to try different routes, an indication that they had superior working memory. In a test of spatial learning and memory, the mice with extra klotho performed twice as well.

Researchers then analyzed the mouse brain tissue and found that the mice with elevated klotho had twice as many GluN2B subunits within synaptic connections. GluN2B is part of the N-methyl-D-aspartate receptor, or NMDAR, a key receptor involved in synaptic plasticity.

The researchers found more GluN2B-containing receptors in the hippocampus and frontal cortex, brain regions that support cognitive functions. When the researchers gave the mice a drug that blocks the action of these receptors, the klotho-enhanced mice lost their cognitive advantage.

Explore further: Loss of anti-aging gene possible culprit in age-related macular degeneration

More information: Cell Reports, Dubal et al.: "Life extension factor klotho enhances cognition." http://www.cell.com/cell-reports/abstract/S2211-1247(14)00287-3

Related Stories

Loss of anti-aging gene possible culprit in age-related macular degeneration

October 8, 2013
A team of researchers at Georgetown University Medical Center (GUMC) has found that loss of an anti-aging gene induces retinal degeneration in mice and might contribute to age-related macular degeneration, the major cause ...

A new treatment for kidney disease-associated heart failure?

January 9, 2013
Chronic kidney disease (CKD) patients frequently suffer from mineral bone disorder, which causes vascular calcification and, eventually, chronic heart failure. Similar to patients with CKD, mice with low levels of the protein ...

New drug target identified for multiple sclerosis and Alzheimer's disease

January 30, 2013
Researchers at Boston University School of Medicine (BUSM) led by Carmela Abraham, PhD, professor of biochemistry, along with Cidi Chen, PhD, and other collaborators, report that the protein Klotho plays an important role ...

Molecular switches age-related memory decline? Genetic variant protect against brain aging

May 6, 2014
Even among the healthiest individuals, memory and cognitive abilities decline with age. This aspect of normal aging can affect an individual's quality of life and capability to live independently but the rate of decline is ...

Recommended for you

Peers' genes may help friends stay in school, new study finds

January 18, 2018
While there's scientific evidence to suggest that your genes have something to do with how far you'll go in school, new research by a team from Stanford and elsewhere says the DNA of your classmates also plays a role.

A centuries-old math equation used to solve a modern-day genetics challenge

January 18, 2018
Researchers developed a new mathematical tool to validate and improve methods used by medical professionals to interpret results from clinical genetic tests. The work was published this month in Genetics in Medicine.

Can mice really mirror humans when it comes to cancer?

January 18, 2018
A new Michigan State University study is helping to answer a pressing question among scientists of just how close mice are to people when it comes to researching cancer.

Group recreates DNA of man who died in 1827 despite having no body to work with

January 16, 2018
An international team of researchers led by a group with deCODE Genetics, a biopharmaceutical company in Iceland, has partly recreated the DNA of a man who died in 1827, despite having no body to take tissue samples from. ...

Epigenetics study helps focus search for autism risk factors

January 16, 2018
Scientists have long tried to pin down the causes of autism spectrum disorder. Recent studies have expanded the search for genetic links from identifying genes toward epigenetics, the study of factors that control gene expression ...

The surprising role of gene architecture in cell fate decisions

January 16, 2018
Scientists read the code of life—the genome—as a sequence of letters, but now researchers have also started exploring its three-dimensional organisation. In a paper published in Nature Genetics, an interdisciplinary research ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

DonaldJLucas
not rated yet May 11, 2014
Other articles show that KLOTHO expresses a protein in tubules in the kidney that then improves memory and learning. Does this mean that if you lack the KL-VS variant and receive a kidney transplant from someone who does possess the KL-VS variant, that you will start overexpressing this protein as well and experience cognitive improvement? That could lead to a number of unintended, but interesting life changing outcomes and maybe a movie or two ;-)

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.