A variant of the gene KLOTHO is known for its anti-aging effects in people fortunate enough to carry one copy. Now researchers find that it also benefits brain function by increasing overall levels of klotho in the bloodstream and brain.

But the improvements in learning and memory associated with klotho elevation aren’t strictly tied to aging. They do occur in aging mice, but also in young animals, according to a report published in the Cell Press journal Cell Reports (open access) on May 8th.

That means klotho works to enhance brain power, but in an unexpected way.

Aging is a primary risk factor for cognitive decline, lead author Dena Dubal explained. The question was: Would a factor known to play a role in long life have benefits for cognition too?

The researchers examined this question in three separate cohorts of people participating in aging studies of various kinds, adding up to more than 700 people. Their analysis showed that people with one of the life-extending variants of the KLOTHO gene scored better on cognitive tests. Because those effects were associated with higher circulating levels of klotho, the researchers turned to genetically engineered mice that express higher-than-normal levels of the life-extending substance.

Indeed, klotho worked there too. “Mice with elevated klotho performed twice as well as controls in some cognitive tests – such as remembering where a hidden platform was located in a water maze,” Dubal said. In other tests, the mice did better too, but in some cases only slightly.

Elevating klotho in mice also enhanced the formation and flexibility of neural connections, the cellular basis for learning and memory. Surprisingly, the effects of klotho were evident in mice young and old. They didn’t correlate with age in humans, either.

In other words, klotho appears to work in a manner independent of aging and may increase cognitive reserve at different life stages. The researchers say that in healthy, aging humans the positive cognitive effects of carrying one copy of the KLOTHO variant may even exceed the harmful effect of carrying the notorious ε4 variant of the APOE gene, best known for its contributions to Alzheimer’s disease.

According to Lennart Mucke of the Gladstone Institute and the University of California, San Francisco, who directed the study, that means the findings could have broad therapeutic implications. “Because cognition is a highly valued aspect of brain function that diminishes with aging and disease, the potential to enhance it even slightly is of great potential relevance to the human condition,” Dubal said.

---

Abstract of Cell Reports paper

• KLOTHO variant elevates klotho levels and is associated with enhanced human cognition
• Elevation of klotho in mice enhances normal cognition, independent of age
• Klotho elevation leads to greater synaptic GluN2B (NMDAR subunit) levels and plasticity
• GluN2B blockade abolishes klotho-mediated effects on NMDAR functions and cognition

Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. 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. 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.