Rare Hormone May Eventually Be A Life Extender for Humans

By Jane Farrell

Klotho, a life-extending protein hormone, occurs in only a minority of people. But eventually, scientists may be able to administer it to others.

Scientists at UC San Francisco found that giving klotho to young, aging or impaired mice rapidly improves their cognitive and physical performance.

While previous studies had revealed associations between elevated klotho levels and better cognition, that research had been done with mice genetically engineered to continuously produce high klotho levels and in people carrying genetic variants that caused them to have high klotho levels throughout life. As a result, it was still unclear whether klotho could be administered like a drug to rapidly enhance cognitive functioning in mice or people with normal or low levels of the hormone.

“The burning question in the field was, ‘Does klotho have therapeutic potential?'” said Dena Dubal, MD, PhD, associate professor of neurology, David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease at UCSF, and senior author of the new paper. “We now know that, yes, it does.”

The study, published online Aug. 8, 2017, in Cell Reports, showed clear evidence of improved cognition across a range of domains – including spatial learning and memory, as well as working memory. But it remains unexplained how the piece of the klotho hormone that the researchers injected into the bodies of the mice caused these effects, since there is no evidence that klotho is able to enter the brain from the bloodstream.

“It makes us wonder about the connection between the body and the brain,” said Dubal, a member of the UCSF Weill Institute for Neurosciences. “What we saw with acute klotho administration may be similar to what happens with exercise, which also improves cognition and brain health, although we don’t know how.”

The beneficial effects that Dubal and her team saw in young mice occurred within hours, and they far outlasted the time that klotho remained active in the body. “It suggests to me that there is a long-lasting effect of even a single treatment, and it probably has to do with the remodeling of synapses, the sites where communication among nerve cells takes place,” she said.

The team also tested aged mice that, at 18 months old, are at about the same stage in the mouse lifespan as a 65-year-old human, and found that a single injection of klotho was enough to significantly improve their ability to navigate and to learn new tasks.

The researchers then looked at mice that were engineered to produce a human protein called alpha-synuclein, which is a hallmark of Parkinson’s disease and contributes to Alzheimer’s disease. Alpha-synuclein is believed to contribute to the movement disturbances seen in Parkinson’s. Giving klotho to these mice improved their motor function. The klotho-treated mice also learned better and were more willing than untreated mice to explore new territory, even though their brains remained loaded with toxic proteins. This suggests that the treatment might somehow make diseased brains more resilient.

Dubal said the new findings, along with others like the experiments involving exercise or those in which older mice have been rejuvenated with blood from younger mice, are helping to illuminate the dimly understood connections between the body and the brain.

“All of this work is going to teach us something really important about how the body transmits resilience to the brain,” she said. “That’s where this is taking us.”