The first primate studies to show the cognitive benefits of the klotho protein could be a step toward clinical applications. Injecting aging monkeys with a ‘longevity factor’ protein can improve their cognitive function, study reveals. The findings, published in Nature Aging could lead to new treatments for neurodegenerative diseases.
This is the first time that restoring the levels of klotho, a naturally occurring protein that declines in our bodies with age, has been shown to improve cognitive abilities in primates. Previous research in mice has shown that klotho injections can extend the animals’ lives and increase synaptic plasticity, the ability to control communication between neurons, at connections called synapses.
“Given the close genetic and physiological parallels between primates and humans, this could suggest potential applications for the treatment of human cognitive disorders,” says Marc Busche, a neuroscientist from the UK Dementia Research Institute group at University College London.
The protein is named after the Greek goddess Clotho, one of the Fates who spins the thread of life.
Monkey memory tests
The study involved testing the cognitive abilities of old rhesus macaques (Macaca mulatta), with an average age of around 22 years, before and after a single injection of klotho. To do this, the researchers used a behavioral experiment to test spatial memory: the monkeys had to remember the location of an edible treat that the investigator had placed in one of several wells after it had been hidden from them.
Study co-author Dena Dubal, a physician-researcher at the University of California, San Francisco, compares the test to remembering where you left your car in a parking lot or remembering a sequence of numbers minutes after hearing them. Such tasks become more difficult with age.
The monkeys performed significantly better in these tests after being given klotho they identified the correct wells about 45% of the time before the injections, compared to about 60% of the time after the injection. The improvement lasted at least two weeks. In contrast to previous studies involving mice, relatively low doses of klotho were effective. This adds an element of complexity to the findings, suggesting a more subtle mode of action than previously thought, says Busche.
Unclear mechanism
It is still not clear exactly how the klotho injection has this effect on cognition or why it takes so long. Klotho cannot cross the blood-brain barrier by itself, and unraveling its mechanism is a matter of finding what intermediates are involved, Dubal explains. But this study “certainly gives us hope,” he says, “and there’s a very strong case for jumping into human clinical trials now.”
Gøril Rolfseng Grøntvedt, a neuroscientist at the Norwegian University of Science and Technology in Trondheim, agrees that more work is needed to answer such questions. Grøntvedt and her team previously found that people with Alzheimer’s disease who have naturally higher levels of klotho tend to experience less cognitive impairment than people with lower levels3.
This raises the possibility that artificially increasing klotho may have beneficial effects. A better understanding of the protein’s mechanism of action will be “crucial” for realizing its clinical potential, says Grøntvedt.
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