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Why a Gene Variant Linked to Longevity Is Associated with Better Cognitive Function

Talan, Jamie

doi: 10.1097/01.NT.0000450998.79976.29
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Investigators have identified a gene variant, klotho, that seems to confer a cognitive benefit in an animal model and may contribute to cognitive reserve in older people.

People who carry a common variant of a gene linked to longevity seem to perform better on a number of cognitive tests, according to a new study by scientists at the Gladstone Institutes and the University of California, San Francisco (UCSF).

The findings, reported in the May 8 issue of Cell Reports, have sparked an interest in testing whether enhancing the klotho protein, an enzyme encoded by the KL gene, could one day enhance cognitive stores in people with Alzheimer's disease (AD) and other conditions that disrupt brain signals that govern learning and memory. Studies are now underway to see whether the klotho gene variant, KL-VS, protects against dementia.

Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease, Dena Dubal, MD, PhD, assistant professor of neurology at UCSF, and their colleagues compared genetic information and results from cognitive tests of language, executive function, visuospatial ability, as well as learning and memory in 718 cognitively fit people between 52 and 85 years old and found that those with the KL-VS variant performed better on all of the cognitive tests.

They also collected blood and found that those with one copy of the genetic variant had 10- to 20-percent more circulating klotho protein than non-carriers. Klotho levels declined in older people, as did its cognitive benefit. The group is now set to study klotho in patients diagnosed with mild cognitive impairment and AD.

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The klotho gene was first identified in the mid-1990s. Since then, scientists have learned that it is produced in the periphery (primarily, the kidney) and in the brain. It is made in the choroid plexus and cranked out into the cerebrospinal fluid that bathes the brain. Nerve cells in the hippocampus also produce low levels of klotho. In the kidney it regulates vitamin D and phosphate metabolism and certain signaling pathways.

To understand how klotho enhances memory and learning, the scientists worked with transgenic mice engineered to overexpress mouse klotho — KL mice. They found that the KL mice performed better on a number of cognitive tasks. The transgenic KL mice produce 2.5 times more klotho protein in the brain and lived longer than wild type mice, according to Dr. Mucke. Year-old KL mice were better at finding the hidden platform on the Morris water maze test compared with mice that produced normal levels of klotho. Young KL mice also did better on cognitive tests than wild type animals.

In humans, the KL-VS variant does not seem to have an effect on age-related cognitive decline, although there is some evidence that the higher klotho levels associated with this genotype increase cognitive reserve, which may also have implications for AD, Dr. Mucke said. This study suggests “the aging brain may still be responsive to klotho,” he added.

So what is the mechanism underlying this effect? The researchers analyzed brain tissue from the wild-type and KL mice, and found that the transgenic mice had twice as many N-Methyl-D-aspartic acid (NMDA) receptors containing GluN2B subunits in synapses, which have been found to play a role in learning and memory. NMDA receptor currents decayed more slowly, and synapses in the hippocampus showed enhanced long-term potentiation. These changes would be expected to make synaptic connections among neurons more adaptable and to promote learning and memory.

When the scientists gave the KL mice a drug that blocked the NMDA-GluN2B receptors, the animals lost their cognitive advantage. Based on these findings, Dr. Dubal, the lead author of the study, suspects that the increase in the NMDA GluN2B receptors is responsible for the improvement in cognitive function.

“Our hope is that increasing klotho levels in aging or disease may also improve cognition,” said Dr. Mucke. They have been working on this objective with Carmela Abraham, PhD, a professor of biochemistry, pharmacology and experimental therapeutics and neuroscience at Boston University School of Medicine. She is a co-author on the Cell Reports paper.

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In 2008, Dr. Abraham and her Boston colleagues reported that klotho expression was downregulated in the brains of aged monkeys and in mouse models of Alzheimer's disease. She then focused on ways to upregulate klotho expression in the brain by searching for small molecule compounds that could be developed into future drugs.

About 20 percent of the human population has one copy of the KL-VS variant. Only 2- to 4-percent have two copies, which Dr. Mucke said has been shown to decrease longevity for unclear reasons.

The scientists are completing a study on AD mouse models to see if overexpressing klotho alters the trajectory of the disease. They are also designing a clinical study to understand the effect the variant has on the development of dementia.

“Cognitive reserve is complex and determined by many different factors,” said Dr. Mucke. “We do not yet know whether the improved performance of KL-VS carriers on cognitive tests translates into a real life advantage in daily living,” he said. Are people with higher klotho levels better off in school and work? “We just don't know.”

And what about later in life? Could klotho have any benefit in slowing age-associated cognitive decline or even dementia? That is one of the questions that Boston's Dr. Abraham has been consumed with since she first started studying about klotho over a decade ago.

In her studies to identify mechanisms that lead to cognitive decline in the aged monkeys, she reported myelin abnormalities in their brains. Her laboratory recently discovered that one of klotho's roles in the brain is to enhance oligodendrocyte maturation and myelination. Findings from the study were published in the January 2013 issue of the Journal of Neuroscience. They have gone on to test overexpression of klotho in an animal model of multiple sclerosis. The transgenic animals had twice as many myelinated axons as wild type mice, she said. She is hoping it could have some therapeutic benefit in MS also.

Dr. Dubal added that understanding klotho could have major implications for brain health. “We know about detrimental genetic influences on aging and cognitive health, such as carrying the apolipoprotein E4 allele. Our discovery that carrying one KL-VS allele may confer beneficial influences on cognition may add to our ability to promote and predict brain health in an emerging era of personalized medicine.” She and her colleagues also found that klotho protected hippocampal neurons from damage following exposure to excess glutamate and oligomeric amyloid beta.

She and her colleagues have done high throughput screens of 150,000 small molecule compounds and identified a few klotho-enhancing molecules that have all of the characteristics they were looking for: stability, good pharmacokinetics, and penetration through the blood-brain barrier. They have also created a molecule that will be used in animal model studies of MS and AD.

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Joseph Martin, MD, PhD, the Edward R. and Anne G. Lefler distinguished professor of neurobiology at Harvard Medical School, studies how the hypothalamus regulates pituitary hormone secretions. He said he would not be surprised if klotho turns out to be a hormone.

“It's a circulating protein that you can find in blood and cerebral spinal fluid,” said Dr. Martin, who focuses his research on neurodegenerative diseases. “It is quite remarkable and surprising. It may function as a hormone-like substance since some would argue that growth hormone declines might contribute to aging and certainly cognitive decline also occurs in diabetics.”

As a scientist who thinks about and creates novel therapeutic approaches to AD, Frank M. Longo, MD, PhD, the George and Lucy Becker professor and chairman of the department of neurology and neurological sciences at Stanford University School of Medicine, said klotho “gives us a new target, a new strategy.”

“It's great science,” he continued. “They went in and saw that klotho is involved in human lifespan but then they find that it is not necessarily associated with enhanced cognition. They discovered something that was not expected. And so they found a new mechanism that enhances synaptic function and cognition. It gives us a novel insight into mechanisms involved in cognition.”

It may even have implications for AD. “Alzheimer's is marked by a decrease in synaptic functioning,” said Dr. Longo. “Targeting klotho improves synaptic functioning and therefore we can begin to ask whether overexpressing or otherwise enhancing klotho might have an effect on the loss of synaptic activity in AD.

“I am always excited about new mechanisms,” he added. Ultimately, “AD may need two or three approaches. It might work.”

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•. Dubal DB, Yokoyama JS, Zhu L, et al. Life extension factor klotho enhances cognition. Cell Rep 2014 E-pub 2014 May 8.
    •. Past research on klotho:
      © 2014 American Academy of Neurology