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 has benefits when it comes to brain function. The variant appears to lend beneficial cognitive effects by increasing overall levels of klotho in the bloodstream and brain.
What's more, 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. That means klotho works to enhance brain power, but in an unexpected way.
"Based on what was known about klotho, we expected it to affect the brain by changing the aging process," said Lennart Mucke of the Gladstone Institute and the University of California, San Francisco, who directed the study. "But this is not what we found, which suggests to us that we are on to something new and different."
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?
Together with a large group of collaborators, Mucke and Dubal examined the 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.
Mucke says 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.