They then injected a single low dose of klotho under the skin of each monkey, raising protein levels to normal levels at birth. After four hours, the researchers had them complete the food-finding task in batches of 20 trials, and the team then retested the monkeys over the next two weeks. Overall, the animals were more likely to make the right choices than they were before receiving the injection. The team tested monkeys with two versions of the task: an easier task with fewer compartments to choose from, and a harder task with more compartments to choose from. Klotho performed about 6 percent better on the easier tasks and about 20 percent better on the harder tasks, Dubal said.
“It’s very encouraging,” said Moy, who was not involved in the new study.
The researchers had the monkeys complete the task multiple times over a two-week period, and the team found that although the klotho was broken down by the body within days of injection, the cognitive-enhancing effects persisted throughout. Eric Verdin, chief executive of the Buck Institute on Aging, said: “The fact that the drug can be given as a single dose for two weeks seems fantastic, although we don’t currently know what to do with repeated doses. Will it work again.” Not involved in the study.
In fact, in previous studies in mice, both low and high doses of klotho boosted cognition, helping them perform better on maze tasks that challenge learning and memory. But when Dubal’s team gave the monkeys doses of 10, 20 and 30 micrograms per kilogram of body weight, the effect leveled off at the 10-microgram dose. That’s an important signal for researchers as they consider testing Cloto injection in humans one day. When it comes to dosage, Welding says, “more isn’t always better.”
People are born with about five times the level of Clotho as an adult, and in monkey experiments, low doses of Clotho were equivalent to infant levels. Dubal speculates that being within and not exceeding doses the body has experienced before may be more important in primates than in mice. The next step will be to test lower doses in human clinical trials to find “the therapeutic sweet spot in humans,” Dubal said. “Maybe brain health needs supplementation, not excess.”
But klotho is a big mystery: No one knows exactly how it works in the brain. “It’s a complete black box,” Welding said. The researchers thought the protein must somehow protect the brain — but how? It appears unable to cross the blood-brain barrier, the semipermeable border of blood vessels and tissues that keeps many harmful substances away from the brain.
Given that Cloto’s cognitive effects outlast its existence in the body, Dubal suspects that it must have an effect on the connections between neurons in the brain, possibly “redesigning synapses to better receive and retain memories,” she says. Her research group is currently working to understand how Clotho gets into the brain, and what it does once it gets there.