Aug 112017
 

Dena Dubal (center), MD, PhD, and her team have discovered that administering a fragment of the klotho protein improves the cognitive and physical performance of mice. Photo by Steve Babuljak

Mice Treated with Klotho Do Better on Tests of Memory and Motor Skills

In a study that augurs well for the therapeutic potential of klotho – a life-extending protein hormone that a minority of people naturally produce at high levels – scientists at UC San Francisco have found that administering a fragment of the klotho protein 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.”

Long-Lasting Effect

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 burning question in the field was, ‘Does klotho have therapeutic potential?’ We now know that, yes, it does.

Dena Dubal, MD, PhD

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.

“There’s stronger and stronger evidence that the body works in a very integrated way, and that systemic effects profoundly affect the resilience of our brain,” Dubal said.

Klotho, which is naturally produced in both the kidney and the brain, is a complex hormone that affects many different systems in the body, and it has several forms. Once produced, it lodges itself in cell membranes, then enzymes cleave off a portion that circulates in the blood and the cerebrospinal fluid that bathes the brain and spinal cord.

The klotho fragment that Dubal’s team injected into mice is similar to the cleaved piece of the hormone that naturally circulates in the blood. But since klotho does not cross the so-called blood-brain barrier, which blocks the entry of some substances from the general circulation into the brain, researchers do not know exactly how it alters brain function.

Previous Work About Genetic Modifications

Members of Dubal’s lab had previously shown that mice carrying genetic modifications that exposed them to high klotho levels from birth had greater numbers of a synaptic protein called the GluN2B subunit, which is implicated in long-term potentiation, a strengthening of synapses that is critical to learning and memory. The researchers leading the current study expected to find a greater abundance of GluN2B in the klotho-treated mice, but they did not.

Instead, “after many months of repeating experiments and analyzing the data, we slowly realized that klotho treatment was increasing activation of the subunits that were already there,” said Julio Leon, PhD, first author and a postdoctoral fellow in Dubal’s lab.

To confirm these findings, the researchers selectively blocked the GluN2B subunits to see if they could still be activated by klotho, and found that they could not. Then they performed an unbiased analysis of about 4,000 proteins to see which ones changed together in the brains of the klotho-treated mice, an analysis that pointed to glutamate receptor signaling, which involves GluN2B, as the main pathway affected by klotho treatment.

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.”

Learn more: Hormone Shows Promise as Cognition Enhancer

 

The Latest on: Klotho
  • Study on mice shows hormone could curb dementia
    on August 17, 2017 at 7:07 pm

    If ever there were a hormone to spark intellectual excitement, it’s klotho. At the dawn of our lives, our blood brims with klotho. But as age and disease stiffen our joints and cloud our minds, klotho ebbs. People who exercise and remain spry into old ... […]

  • Mice study shows potential of protein hormone as cognition enhancer
    on August 15, 2017 at 4:35 pm

    SAN FRANCISCO, Aug. 15 (Xinhua) -- Researchers at the University of California, San Francisco, have found that administering a fragment of the klotho - a life-extending protein hormone that a minority of people naturally produce at high levels - to young ... […]

  • Shot of Klotho Boosts Memory In Aging and Diseased Mice
    on August 15, 2017 at 9:19 am

    Talk about instant gratification. According to an August 8 paper in Cell Reports, injecting a fragment of the protein klotho markedly improves memory and motor function in mice. Klotho is a protein associated with cognitive function in people, and reported ... […]

  • Klotho Protein Fragment Improves Brain Function, Resilience in Mice; May Eventually Benefit Parkinson’s Patients
    on August 14, 2017 at 6:11 am

    The naturally-occurring protein α-klotho improves cognition and brain resilience in mice, and may have potential benefits for Parkinson’s disease (PD) and Alzheimer’s disease (AD), researchers showed. The research was led by Dena B. Dubai, an MD and ... […]

  • Klotho Protein Fragment (αKL-F) Could Improve Cognition
    on August 12, 2017 at 3:27 am

    Patients who have high klotho levels appear to have better cognitive functions Exogenous administration of klotho improved cognitive function in mice It improved cognition and motor function in mice with high α-synuclein levels, a protein whose levels are ... […]

  • Hormone Shows Promise as Cognition Enhancer
    on August 10, 2017 at 1:42 pm

    Summary: Researchers report klotho, a life extending protein, improved working memory, spatial memory and learning in mice. The researchers also noted a single injection of klotho was sufficient to improve cognitive ability and the effects were long lasting. […]

  • An extra dose of this longevity hormone helped make mice smarter
    on August 9, 2017 at 1:44 pm

    Klotho, in ancient Greek mythology, is one of the Fates controlling the span of human destiny tasked as she was with cutting the string that determined the length of a person’s life. Klotho is also a naturally occurring hormone in the body. More than two ... […]

  • Klotho longevity hormone helped make mice smarter
    on August 9, 2017 at 1:00 am

    Researchers injected three types of mice with a portion of the protein. They injected young mice, aged mice, and mice genetically altered to have brains similar to that which we would see in Alzheimer’s or Parkinson’s patients in humans. “Within ... […]

  • Possible Anti-Aging Brain Therapy Shows Promise in Mice
    on August 8, 2017 at 1:00 am

    Researchers discovered the klotho protein in 1997, when they found that diminished levels seemed to make the animals age faster. Conversely, mice genetically engineered to maintain elevated klotho levels live 30 percent longer than normal mice. Recent ... […]

  • Longevity hormone boosts memory and protects against brain aging in mice
    on August 7, 2017 at 5:00 pm

    In a study that augues well for the therapeutic potential of klotho -- a life-extending protein hormone that a minority of people naturally produce at high levels -- scientists have found that administering a fragment of the klotho protein to young ... […]

via Google News and Bing News

Leave a Reply

%d bloggers like this: