A fateful gene may make us smarter - for a while, at least

Dena Dubal and Jennifer Yokoyama have been plucking at the thread of fate. The researchers at UC San Francisco are fascinated with a longevity gene named for one of the Greek Fates, Klotho.

“She spins the thread of life and she is the daughter of Zeus,” said Dubal, a physician and neurologist at the university’s Memory and Aging Center. “And we have expanded her duties to include boosting brain function.”

In a study of more than 400 aging people, the UC San Francisco researchers suggest that having a single copy of one variety of that gene seems to give people better executive function and more gray matter in an area prone to the ravages of time. The study was published online Tuesday in the journal Annals of Clinical And Translational Neurology.

Their findings may not help us live longer – yet – but could offer some insight into easing the effects of degenerative disorders of the brain, such as Alzheimer’s and Parkinson’s diseases.

Japanese scientists first discovered the Klotho gene in 1997, in a mouse, when they accidentally inserted some DNA code and gummed up its protein-making factory. The mouse suddenly aged, showing signs of hardened arteries, porous bones, atrophied muscles and other indignities of age. Enhancing that gene appeared to do the opposite: prolong the life of the rodent.

Since then, researchers have linked the human equivalent of the gene with longevity and improved kidney and heart function. Last year, the UC San Francisco researchers showed that a protein produced by this gene variant correlated with higher cognitive function, both in mice and humans.

“Not only did they live longer, but they were smarter,” Dubal said. “And they were smarter across the life span, from the young to older ages.”

But the gene variant is no fountain of youth. How it works remains largely as inscrutable as the Fate for which it was named.

Dubal and Yokoyama have focused on the variant of the gene known as the KL-VS haplotype. Genes come in pairs, but when this variant is paired with another that is not identical, it appears to work wonders, largely through higher production of a protein that performs multiple regulatory functions in the body.

“Interestingly, if you have two copies of this variant it’s been associated with shorter life span,” said Yokoyama, who studies neurogenetics.

About 20% of us have one copy of that variant, while most of the rest of us have other variations. Only about 3% of the population has the apparent misfortune of having identical twins of the gene variant.

Adding to the complexity is the fact that klotho, the protein, does a lot of things in the body, not all of them tied to aging. Reduced klotho in embryonic mice leads to early postnatal death, poorly formed brain cells and cognitive impairment – suggesting that it has something to do with the early development of the brain.

That’s what interests Dubal’s UC San Francisco lab. This time, they looked at a specific area of the cortex. In tests of two groups of more than 200 people each, they found that people with the single copy of the gene variant scored higher than others in tests of working memory, task inhibition and processing speed - crucial ingredients to executive function. And a frontal area that is vital to executive function and is linked to many types of cognition was larger, the study found.

Again, having two identical copies of the gene variant brought scores and gray matter volume down relative to the one-copy or no-copy groups, continuing a paradox shown in previous studies.

Still, Klotho does not appear to be slowing down shrinkage of the brain over time; it just may give the lucky few more gray matter to lose, according to the study.

“By having a reserve there of resilience, maybe individuals would be buffered against effects of diseases, such as Alzheimer’s, Parkinson’s or schizophrenia.” Dubal said.

Building or shoring up that reserve might mitigate some of the symptoms of neurodegenerative disease, the researchers suggest.

“The idea would be if somehow we could increase levels of the klotho protein, similarly to how the genetic variant does, then this perhaps could have a similar effect in augmenting cognition or providing some sort of reserve against disease,” Yokoyama said.

A lot of unknowns remain to be examined, the researchers cautioned. They want to look more closely at the molecular workings of the gene variants and proteins, using mice, and peer more closely into functional differences in the brains of humans with the lucky gene type.

And the genome probably has other things in common with Greek mythology. After all, Klotho had two sister Fates. One measured out the length of the string, and the other snipped it.

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