Klotho, the ancient Greek goddess of fate, is responsible for spinning the thread of life. In the human body, a protein of the same name might also be able to bring some life back to an aging brain.
In a study published today in the journal Nature Aging, researchers at Yale and the University of California, San Francisco found that a single injection of the klotho protein led to modest improvements in cognitive function in older monkeys and that the effects were twofold. lasted for weeks. The authors think the protein is a promising avenue for research into rejuvenating brain function in older adults.
“Cognitive decline from aging is one of our most pressing biomedical problems with no truly effective drugs,” said Dena Dubal, a UCSF professor of neurology and the study’s lead author. After discovering – accidentally – in previous work that klotho stimulates cognition in mice, she says, “it became important to test this in a brain like ours.”
Produced by the kidney, klotho circulates in the blood and has been associated with health and longevity. Orson Moe, a kidney specialist and professor of internal medicine at the University of Texas Southwestern Medical Center, describes it as a housekeeper that helps regulate the kidneys and metabolism. “It protects us and keeps us healthy,” he says.
The protein was first discovered in 1997 by pathologist Makoto Kuro-o of the National Institute of Neuroscience in Tokyo. He showed that mice without klotho suffered from what he called a “syndrome similar to aging in humans.” They had heart disease, cancer, cognitive decline and early stage organ failure. Kuro-o later discovered that mice that produced more klotho lived 20 to 30 percent longer than mice with normal levels.
In humans, having more of the protein appears to have health benefits. Although klotho levels naturally decrease with age, some people have more of them than others. In a 2014 paper, Dubal and her colleagues studied more than 700 participants between the ages of 52 and 85. Those with higher levels of the protein — about one in five people studied — performed better on thinking and memory tests, such as drawing a picture recalled and naming the color of a word represented in a different color.
For that study with mice, the team also developed mice with a higher than normal protein content. These mice performed better on maze tests than normal mice.
In the current study, Dubal and her coauthors wanted to see if klotho would have the same effects on monkeys, which are often used as a substitute for humans because of their genetic similarities. As people age, their working memory, the ability to hold something in mind, such as a phone number, deteriorates. Dubal’s research team tested the working memory capacity of 18 rhesus macaques, whose age was roughly equivalent to 65 in human years. Each had to remember the location of a hidden tidbit in a series of compartments — a common lab test the researchers chose because it relies on working memory and doesn’t get any easier over time.
They then administered a single low dose of klotho under each monkey’s skin, raising levels of the protein to levels normally present at the animals’ birth. Four hours later, researchers had them complete the food-finding task in batches of 20 trials, and the team then tested the monkeys again over the next two weeks. In general, the animals made the right choices more often than before they received the injection. The team tested monkeys on two versions of the task: an easier one, where there were fewer compartments to choose from, and a more difficult one with more. Klotho improved their performance on the easier task by about 6 percent and on the harder version by about 20 percent, says Dubal.
“This is very encouraging,” says Moe, who was not involved in the new study.
The researchers got the monkeys to perform the task several times over the course of two weeks, and the team saw that although klotho is broken down by the body within a few days of injection, the cognitive-enhancing effect persisted throughout. “The fact that it can be given once and last for two weeks seems great, although at this point we don’t know if repeated dosing would work again,” said Eric Verdin, CEO of the Buck Institute for Research on Aging, who was not involved at the study.
In previous studies on mice, both low and high doses of klotho boosted cognition, allowing them to perform better in a variety of maze tasks that challenge learning and memory. But when Dubal’s team gave monkeys doses of 10, 20 and 30 micrograms per kilogram of body weight, the benefits plateaued at the 10 microgram dose. This raises an important flag for researchers as they consider testing klotho injections in humans someday. When it comes to dosing, Verdin says, “More isn’t always better.”
