Longevity Gene May Boost Cognitive Function

Megan Brooks

May 12, 2014

A common variant of a gene associated with longevity may also improve learning and memory — and 1 in 5 people have it, a new study shows.

In 3 independent cohorts and a meta-analysis, having a single copy of the KL-VS variant of the klotho gene was associated with enhanced cognitive performance on standard tests, independent of other relevant factors, the researchers say.

"It is tempting to speculate that increasing klotho levels or simulating its cognition-enhancing activities with drugs might increase cognitive functions and help ameliorate deficits in cognitive disorders such as Alzheimer's disease or schizophrenia," senior author Lennart Mucke, MD, director, Gladstone Institute of Neurological Disease and distinguished professor of neuroscience, University of California San Francisco (UCSF), told Medscape Medical News.

"We have long known about detrimental genetic influences on cognitive health, such as carrying the APOE ε4 allele. The finding that carrying 1 KL-VS allele may confer benefits to cognitive functions may add to our understanding of predicting and promoting brain health in aging and disease — particularly in an emerging era of personalized medicine," lead author Dena Dubal, MD, PhD, assistant professor of neurology, the David A. Coulter endowed chair in aging and neurodegeneration at UCSF, added in comments to Medscape Medical News.

Their study was published May 8 in Cell Reports.

Thread of Life

The klotho gene was discovered in 1997 and named for the Greek mythologic goddess of fate, who spins the thread of life. It's an aging regulator that, when overexpressed, extends lifespan, and, when disrupted, accelerates aging, the researchers note.

It's been shown that higher klotho levels increase lifespan in mice and nematodes. In people, a single allele of the KL-VS variant of klotho promotes longevity and reduces age-related heart disease.

In the current study, the researchers found that people who had 1 copy of the KL-VS variant performed better on a battery of cognitive tests than those who did not have it, regardless of age, sex, or the presence of the APOE ε4 allele, the main genetic risk factor for Alzheimer's disease.

More than 700 people, aged 52 to 85 years, were tested as part of 3 studies. None had any sign of dementia. Consistent with previous studies, 20% to 25% of the patients had 1 copy of the KL-VS variant. 

The researchers also report that transgenic mice with systemic overexpression of klotho performed better than controls in multiple tests of learning and memory. Increasing klotho levels in mice enhanced synaptic plasticity and enriched synaptic GluN2B, an N-methyl-D-aspartate subunit with fey functions in learning and memory, they say.

"Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process," the researchers note in their article. "Augmenting klotho or its effects may enhance cognition at different life stages and counteract cognitive decline," they write.

Dr. Mucke noted that studies are underway to explore the therapeutic potential of klotho. "We are also working hard to further unravel the mechanisms by which klotho enhances cognitive functions and by which aging and disease reduce klotho levels in the brain," he said.

"We are investigating in humans how carrying the KL-VS variant of the klotho gene influences anatomy and network connections of the normal, aging, and diseased brain," Dr. Dubal added. "It will be important to also determine how this variant may alter risks or benefits to cognition in a wide range of neurological disorders," she said.

The study was funded by the Coulter-Weeks Foundation, the SD Bechtel, Jr., Foundation, the National Institutes of Health, the MetLife Foundation, the American Federation for Aging Research, and the Hillblom Aging Network. The authors have disclosed no relevant financial relationships.

Cell Rep. Published online May 8, 2014. Abstract

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