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First primate studies to show cognitive benefits of the protein klotho could be a step towards clinical applications.
Old rhesus monkeys perform better in memory tests after being given an injection of klotho. Credit: Arno Burgi/AFP via Getty
Injecting ageing monkeys with a ‘longevity factor’ protein can improve their cognitive function, a study reveals.
The findings, published on 3 July in Nature Aging1, could lead to new treatments for neurodegenerative diseases.
It is the first time that restoring levels of klotho — a naturally occurring protein that declines in our bodies with age — has been shown to improve cognition in a primate. Previous research on mice had shown that injections of klotho can extend the animals’ lives and increases synaptic plasticity2 — the capacity to control communication between neurons, at junctions called synapses.
“Given the close genetic and physiological parallels between primates and humans, this could suggest potential applications for treating human cognitive disorders,” says Marc Busche, a neurologist at 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.
The study involved testing the cognitive abilities of old rhesus macaques (Macaca mulatta), aged around 22 years on average, before and after a single injection of klotho. To do this, researchers used a behavioural experiment to test for spatial memory: the monkeys had to remember the location of an edible treat, placed in one of several wells by the investigator, after it was hidden from them.
Study co-author Dena Dubal, a physician-researcher at the University of California, San Francisco, compares the test to recalling where you left your car in a car park, or remembering a sequence of numbers a couple of minutes after hearing it. Such tasks become harder with age.
The monkeys performed significantly better in these tests after receiving klotho — before the injections they identified the correct wells around 45% of the time, compared with around 60% of the time after injection. The improvement was sustained for at least two weeks. Unlike in previous studies involving mice, relatively low doses of klotho were effective. This adds an element of complexity to the findings, which suggests a more nuanced mode of actions than was previously thought, Busche says.
It is still unclear exactly how injecting klotho has this effect on cognition or why it lasts this long. Klotho itself cannot cross the barrier from blood to brain, and uncovering its mechanism is a matter of finding what intermediates are involved, explains Dubal. But this study “certainly gives us hope”, she says, “and there’s a very strong reason to jump into human clinical trials now”.
Gøril Rolfseng Grøntvedt, a neurologist at the Norwegian University of Science and Technology in Trondheim, agrees that further work is needed to answer such questions. Grøntvedt and her team previously found that people with Alzheimer’s who have naturally higher klotho levels tend to experience less cognitive impairment than do those with lower levels3.
This raises the possibility that artificially increasing klotho might have beneficial effects. A better understanding of the protein’s mode of action will be “crucial” for realizing its clinical potential, Grøntvedt says.
